Metabolic and neuromodulatory basis of altered activated and deactivated cortical areas in healthy human aging

项目摘要/摘要 人类的健康衰老与认知、记忆和处理效率的下降有关。二 解释功能改变的主要理论是线粒体衰老理论，在衰老理论中线粒体丢失 提供足够的能量来支持功能和改变GABA/谷氨酸神经调节的能力。 校准功能磁共振成像(Fmri)的最新发展使得直接成像神经元的改变成为可能。 衰老中的活动。令人惊讶的是，对任务引起的氧化代谢变化的测量(ΔCMRO2) 发现尽管衰老时基线CMRO2较低，但神经元激活增加。 我们建议通过使用一种新的校准fMRI、功能性1H-MRS的组合来解决这一矛盾 (FMRS)和1H[13C]-MRS方法直接测试线粒体老化和神经调节在脑损伤中的作用 健康的衰老。我们的总体假设是：(I)健康人群中矛盾的功能反应增强 主要在感觉区域观察到的衰老是对较低基线CMRO2的补偿，但这是不够的 为神经元功能提供与年轻受试者相同的能量支持(线粒体衰老理论)； 和(Ii)在年轻人中建立的GABA浓度和BOLD激活之间的反向关系 受试者在老年人中变得迟钝(神经调节理论)。我们将用三个具体目标来检验这些假说。 在目标1中，我们将使用一种新的无气体校准的功能磁共振方法来测量视觉响应的ΔCMRO2 任务在健康的青年和老年受试者中。在目标2中，我们将在校准fMRI的同时进行FMR 抑制性GABA和兴奋性谷氨酸的测定。在目标3中，我们将具体使用1H[13C]-MRS to 测量神经元的CMRO2(通过TCA循环)，我们显示在老化的视皮层中选择性地降低。 在测试像视觉皮质这样的大脑激活区域的变化的同时，我们还将执行 同样的测量同时在后扣带皮质(PCC)进行，它是大脑的主要中枢。 已显示在任务期间停用的默认模式网络(DMN)。静息状态下的功能磁共振成像研究 随着年龄的增长，DMN的连通性发生了改变，但还没有关于其任务的研究 使用定量fMRI或FMRS方法进行响应。了解代谢和神经调节 激活和去激活区域的差异对于理解改变的基础至关重要 健康老龄化中的功能反应。拟议中的工作对人类健康具有很高的潜在意义 为了了解衰老过程中神经元活动变化背后的基本机制，并验证 新的多模式MRI/MRS生物标志物用于评估这些机制和潜在的评估 对机制靶向治疗的反应。虽然1H[13C]-MRS还没有广泛应用，但我们会 评估根据校准的fMRI确定的静息神经元CMRO2是否提供了类似的结果。因为 校准后的fMRI方法不需要吸入气体，它广泛适用于患者群体。

Project Summary/Abstract Human healthy aging is associated with declines in cognition, memory, and processing efficiency. Two leading theories to explain altered function are the mitochondrial theory of aging, in which mitochondria lose the ability to provide sufficient energy to support function and altered GABA/glutamate neuromodulation. Recent developments in calibrated functional MRI (fMRI) have allowed direct imaging of alterations in neuronal activity in aging. Surprisingly, measurements of task-induced changes in oxidative metabolism (ΔCMRO2) have found increased neuronal activation despite lower baseline CMRO2 in aging. We propose to address this paradox, by using a novel combination of calibrated fMRI, functional 1H-MRS (fMRS), and 1H[13C]-MRS approach to directly test the roles of mitochondrial aging and neuromodulation in healthy aging. Our general hypotheses are: (i) The paradoxical increased functional response in healthy aging, observed primarily in sensory areas, is a compensation for lower baseline CMRO2, but it is not sufficient to achieve the same energetic support for neuronal function as in young subjects (mitochondrial aging theory); and (ii) The inverse relationship between GABA concentration and BOLD activation established in young subjects is blunted in elderly (neuromodulation theory). We will test these hypotheses with three specific aims. In Aim 1 we will use a novel gas-free calibrated fMRI method to measure ΔCMRO2 in response to visual task in healthy young and aged subjects. In Aim 2 we will perform, in parallel with calibrated fMRI, fMRS measurements of inhibitory GABA and excitatory glutamate. In Aim 3 we will use 1H[13C]-MRS to specifically measure neuronal CMRO2 (via the TCA cycle) which we showed is selectively decreased in aging visual cortex. In parallel with our testing of changes in activated brain regions like the visual cortex, we will also perform the same measurements simultaneously in the posterior cingulate cortex (PCC), which is a major hub of the default mode network (DMN) that has been shown to deactivate during tasks. Resting-state fMRI studies in aging have shown that the DMN connectivity is altered, but there have been no studies looking at its task response using quantitative fMRI or fMRS methods. Understanding the metabolic and neuromodulatory differences across activated and deactivated areas are crucial for understanding the basis of the altered functional response in healthy aging. The proposed work has high potential human health significance both for understanding basic mechanisms behind the alterations in neuronal activity in aging and in validating a novel multi-modal MRI/MRS biomarker for evaluating these mechanisms and potentially assessing the response to mechanism targeted therapeutics. Although 1H[13C]-MRS is not yet broadly available, we will evaluate whether neuronal CMRO2 at rest determined from calibrated fMRI provides similar results. Because the calibrated fMRI method does not require gas inhalation, it is broadly applicable to patient populations.