Neuroimaging Assessments of Brain Integrity in Aging Mice

描述（由申请人提供）：我的研究生涯的长期目标是使用最先进的，非侵入性脑成像方法（磁共振成像和光谱（MRI/MRS）和正电子发射断层扫描（PET））来评估健康衰老和年龄相关神经退行性疾病动物模型中的脑代谢，血液动力学和神经元（结构和功能）完整性及其与认知功能的关联。我的培训计划的目标是：1)将用于评估血液动力学和代谢的神经影像学方法从人类“反向翻译”到啮齿动物模型；2)通过啮齿动物模型接受衰老生物学方面的培训，重点是代谢生理学；3)将这些新发现的技术应用于研究衰老的作用机制和热量限制（CR）的潜在保护作用；4)对啮齿动物进行行为测试的实践培训，并确定成像与行为结果之间的联系。本研究的目的是利用高场MRI/MRS和PET来研究衰老小鼠的脑完整性，并确定CR可能的保护作用。在大脑中，线粒体葡萄糖氧化磷酸化是主要的能量来源（ATP产生），支持能量需求（维持神经元完整性和基础放电率）。随着年龄的增长，大脑和其他器官的功能丧失，一个被广泛接受的原因是大脑代谢减少。为了支持这一观点，大量神经影像学研究表明，脑氧代谢率（cro2）、葡萄糖代谢率（CMRGlc）和脑血流量（CBF）随着年龄的增长而下降，在神经退行性疾病（如阿尔茨海默病（AD））中下降得更快、更深刻。因此，人们普遍认为，保持生物能量（即葡萄糖氧化能力）对于优化寿命和健康寿命至关重要。干预措施已被引入以保持衰老过程中的代谢。CR可能是各种长寿模式生物中研究得最多的一种，包括酿酒酵母、秀丽隐杆线虫、啮齿动物和猴子。在神经系统中，CR已被证明可以减轻与年龄相关的代谢功能障碍和神经肌肉突触丧失，并增强认知功能。因此，本研究的基本原理是利用无创、多模态神经成像方法表征CR对衰老过程中体内脑代谢、血流动力学和神经元（结构和功能）完整性的影响，以及神经成像指标与认知测试的关联。该研究的中心假设是：正常衰老过程中，大脑代谢功能下降，导致大脑结构、功能和认知完整性降低；CR干预小鼠显示：cmo 2、CBF、CMRGlc、总ATP浓度保持不变；因此，在衰老过程中保留了大脑结构，功能连接和认知能力。该假设将通过三个具体目标进行验证：1)确定正常衰老对脑代谢和血流动力学完整性的影响以及可能的CR保护作用；2)确定正常衰老对神经元（结构和功能）完整性的影响以及CR可能的保护作用；3)确定正常衰老对认知完整性的影响以及CR可能的保护作用。该方法具有创新性，因为它采用无创神经影像学方法研究了衰老过程中CR对体内脑代谢的保护作用；它首次使用互补的、多参数的、无创的成像方法（MRI、MRS和PET）来探索线粒体改变的生理效应；它使用了超高场（11.7T）和啮齿动物的定量成像技术（由PI为人类开发），这是第一次这样做；它会的

DESCRIPTION (provided by applicant): The long-term goal of my research career is to use state-of-the-art, non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic, hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to "reversely translate" the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models; 2) to receive training in the biology of aging using rodent models, with an emphasis on metabolic physiology; 3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR); and, 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR. In the brain, mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production), supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging, both in the brain and in other organs, is decreased brain metabolism. In support of this viewpoint, a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2), glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders, such as Alzheimer's Disease (AD). It is generally believed, therefore, that preserving bioenergetics (i.e., glucose oxidative capacity) is critical fr optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity, including Saccharomyces cerevisiae, Caenorhabditis elegans, rodents and monkeys. In the neuronal system, CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function. The rationale of the study, therefore, is to characterize the effect of CR on in vivo brain metabolic, hemodynamic, and neuronal (structural and functional) integrity in aging using non-invasive, multimodal neuroimaging methods, and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline i normal aging and consequently reduce brain structural, functional and cognitive integrity; mice with CR intervention will demonstrate: preserved CMRO2, CBF, CMRGlc, total ATP concentration; and, thus preserved brain structure, functional connectivity, and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR; 2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR; and, 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative, because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods; it uses complementary, multi- parametric, non-invasive imaging methods (MRI, MRS and PET) to explore the physiological effects of mitochondrial alterations, for the first time; it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents, the first time this has been done; and, it will be the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders, disease progression and treatment efficacy can be monitored non-invasively and nondestructively; 2) the interplay between brain metabolic, structural and cognitive functions in aging can be identified; and, 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans. Collectively, the training provide by the Career Development Award will place me at the cutting edge of aging research, of animal neuroimaging, and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.