Neuroimaging Assessments of Brain Integrity in Aging Mice

描述(申请人提供)：我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(磁共振成像和波谱(MRI/MRS)和正电子发射断层扫描(PET))，在健康老龄化和年龄相关神经退行性疾病的动物模型中评估大脑代谢、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系。我的培训计划的目标是：1)将用于评估血液动力学和新陈代谢的神经成像方法从人类“反向转换”到啮齿动物模型；2)使用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)将这些新发现的技能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；以及4)在啮齿动物的行为测试方面进行实践培训，并确定成像和行为结果之间的联系。这项建议的研究目的是使用高场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，葡萄糖的线粒体氧化磷酸化是主要的能量来源(ATP生产)，支持能量需求(维持神经元的完整性和基础放电频率)。人们普遍认为，大脑和其他器官随年龄增长而出现的功能丧失的原因是大脑新陈代谢减退。为了支持这一观点，许多神经影像研究表明，大脑的氧代谢率(CMRO2)、葡萄糖代谢率(CMRGlc)和脑血流量(CBF)随着年龄的增长而下降，在阿尔茨海默病(AD)等神经退行性疾病中下降得更快、更严重。因此，人们普遍认为，保存生物能量学(即葡萄糖的氧化能力)是优化寿命和健康寿命的关键。为了保护衰老过程中的新陈代谢，已经引入了干预措施。CR可能是对各种延长寿命的模式生物研究最充分的一种，包括酿酒酵母、秀丽线虫、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丢失，并增强认知功能。因此，这项研究的基本原理是使用无创、多模式的神经成像方法来表征CR对衰老过程中活体脑代谢、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系。这一建议的中心假设是，大脑代谢功能将在正常衰老时下降，从而降低大脑结构、功能和认知的完整性；CR干预的小鼠将证明：保存了CMRO2、CBF、CMRGlc、总ATP浓度；从而在衰老过程中保存了脑结构、功能连通性和认知。该假说将通过三个具体目标进行验证：1)确定正常老化对大脑代谢和血流动力学完整性的影响以及CR可能的保护作用；2)确定正常老化对神经元(结构和功能)完整性的影响和CR可能的保护作用；以及3)确定正常老化对认知完整性的影响和CR可能的保护作用。这种方法是创新的，因为它用非侵入性神经成像方法研究了CR对衰老过程中活体大脑代谢的保护作用；它首次使用互补的、多参数的非侵入性成像方法(MRI、MRS和PET)来探索线粒体变化的生理效应；它使用了定量成像技术(由PI为人类开发)，在超高场(11.7T)和啮齿动物中，这是第一次做到这一点；它将 这是第一个在CR小鼠模型中研究认知效应(记忆和空间信息处理)与脑成像结果之间相关性的研究。这项拟议的研究意义重大，因为1)可以非侵入性和非破坏性地监测衰老过程中代谢变化和与年龄相关的神经元疾病、疾病进展和治疗效果的生理效应；2)可以确定衰老过程中大脑代谢、结构和认知功能之间的相互作用；以及3)这些多尺度成像方法可以无缝地从啮齿动物移植到非人类灵长类动物和人类。总的来说，职业发展奖提供的培训将使我处于衰老研究、动物神经成像及其组合的前沿：衰老的翻译神经成像。翻译神经成像是一个非常有前途的新兴领域。我的抱负是成为这一新兴学科的先锋。

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.