Neuroimaging Assessments of Brain Integrity in Aging Mice

衰老小鼠大脑完整性的神经影像评估

• 批准号: 8529429
• 负责人: Ai-Ling Lin
• 金额: $ 9.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529429
• 关键词: Age; Age-Months; Aging; Aging-Related Process; Alzheimer' s Disease; Animal Experimentation; Animal Model; Area; Atrophic; Attenuated; Behavioral; Biochemical Pathway; Bioenergetics; Biological Preservation; Biology of Aging; Brain; Brain imaging; Brain region; Caenorhabditis elegans; Caloric Restriction; Cerebrovascular Circulation; Cerebrum; Cognition; Cognitive; Discipline; Disease; Disease Progression; Dopamine D2 Receptor; Energy-Generating Resources; Exhibits; Functional disorder; Glucose; Glutamates; Goals; Health; Hippocampus (Brain); Human; Image; Imaging Techniques; Impaired cognition; Intervention; Investigation; K-Series Research Career Programs; Learning; Life; Longevity; Magnetic Resonance Imaging; Measurement; Measures; Memory; Metabolic; Metabolism; Methods; Metric; Mitochondria; Monitor; Monkeys; Mus; Neurodegenerative Disorders; Neurons; Organ; Outcome; Oxidative Phosphorylation; Oxygen; Performance; Physiological; Physiology; Positron-Emission Tomography; Production; Prosencephalon; Published Comment; Relative (related person); Research; Resolution; Rest; Rodent; Rodent Model; Saccharomyces cerevisiae; Spectrum Analysis; Structure; Synapses; System; Technology; Testing; Time; Training; Training Programs; Translating; Treatment Efficacy; age related; aged; aging brain; anti aging; behavior test; brain metabolism; brain volume; career; cognitive function; functional loss; gray matter; healthy aging; hemodynamics; imaging modality; in vivo; indexing; information processing; innovation; interest; morris water maze; mouse model; neuroimaging; neuromuscular; nonhuman primate; normal aging; protective effect; public health relevance; skills; white matter

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.

描述（由申请人提供）：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（磁共振成像和光谱学（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动物模型中的大脑代谢、血流动力学和神经元（结构和功能）完整性及其与认知功能的关联 神经退行性疾病。我的培训计划的目标是：1）将用于评估血流动力学和新陈代谢的神经影像方法从人类“反向翻译”到啮齿动物模型； 2) 使用啮齿动物模型接受衰老生物学培训，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； 4）对啮齿类动物进行行为测试的实践培训，并确定成像和行为结果之间的关联。本提案的研究目标是利用高场 MRI/MRS 和 PET 来研究衰老小鼠的大脑完整性，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 产生），支持能量需求（维持神经元完整性和基础放电率）。大脑和其他器官随着衰老而出现功能丧失的一个被广泛接受的原因是大脑新陈代谢的下降。为了支持这一观点，大量神经影像学研究表明，大脑中氧（CMRO2）、葡萄糖（CMRGlc）和脑血流量（CBF）的代谢率随着年龄的增长而下降，并且在神经退行性疾病（例如阿尔茨海默氏病（AD））中下降得更快、更深刻。因此，人们普遍认为，保持生物能（即葡萄糖氧化能力）对于优化寿命和健康至关重要。已采取干预措施来保护衰老过程中的新陈代谢。 CR 或许是对多种长寿模型生物研究最深入的一种，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损失，并增强认知功能。 因此，该研究的基本原理是利用非侵入性、多模式神经影像方法以及神经影像指数与认知测试的关联来表征衰老过程中 CR 对体内大脑代谢、血流动力学和神经元（结构和功能）完整性的影响。该提案的中心假设是，在正常衰老过程中，大脑代谢功能会下降，从而降低大脑结构、功能和认知完整性； CR干预的小鼠将表现出：保留的CMRO2、CBF、CMRGlc、总ATP浓度；从而在衰老过程中保留了大脑结构、功能连接和认知。该假设将通过追求三个具体目标进行检验：1）确定正常衰老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，采用非侵入性神经影像方法研究CR对衰老过程中体内脑代谢的保护作用；它首次使用互补、多参数、非侵入性成像方法（MRI、MRS 和 PET）来探索线粒体改变的生理效应；它使用超高场（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；并且，它将 是第一项在 CR 小鼠模型中调查认知效应（记忆和空间信息处理）与脑成像结果之间相关性的研究。拟议的研究具有重要意义，因为1）可以非侵入性和非破坏性地监测衰老和与年龄相关的神经元疾病中代谢改变的生理影响、疾病进展和治疗效果； 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； 3）这些多度量成像方法可以从啮齿类动物无缝转化为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、动物神经影像学及其组合：衰老转化神经影像学的前沿。转化神经影像学是一个具有非凡前景的新兴领域。我的目标是成为这个新兴学科的先驱。