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

健康人类衰老过程中激活和失活皮质区域改变的代谢和神经调节基础

• 批准号: 10647162
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 65.69万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647162
• 关键词: Address; Age; Aging; Area; Biological Markers; Brain; Brain region; Cell Respiration; Citric Acid Cycle; Cognition; Development; Elderly; Financial compensation; Functional Magnetic Resonance Imaging; Gases; Glutamates; Health; Human; Image; Inhalation; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Methods; Mitochondria; Neurons; Physiological; Rest; Role; Sensory; Testing; Visual; Visual Cortex; Work; aged; aging brain; cingulate cortex; gamma-Aminobutyric Acid; healthy aging; loss of function; memory process; multimodality; neuroregulation; novel; novel therapeutics; patient population; response; targeted treatment; theories

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.

项目摘要/摘要 人类健康衰老与认知，记忆和加工效率的下降有关。二 领导理论解释改变功能的是衰老的线粒体理论，线粒体丧失 提供足够能量来支持功能并改变GABA/谷氨酸神经调节的能力。 校准功能性MRI（fMRI）的最新发展允许直接成像神经元的变化 衰老的活动。令人惊讶的是，任务引起的氧化代谢变化的测量（ΔCMRO2）具有 发现在衰老中，神经元激活目的地较低基线CMRO2。 我们建议通过使用校准的fMRI，功能性1H-MRS的新型组合来解决这一悖论 （FMR）和1H [13C] -MRS方法直接测试线粒体衰老和神经调节的作用 健康衰老。我们的一般假设是：（i）健康中悖论的功能响应 在感觉区域观察到的衰老是较低基线CMRO2的补偿，但还不够 为了获得与年轻受试者相同的神经元功能的能量支持（线粒体老化理论）； （ii）在年轻人中建立的GABA浓度与大胆激活之间的反比关系 在古老的（神经调节理论）中，受试者被钝化。我们将以三个特定目标来检验这些假设。 在AIM 1中，我们将使用一种新型的无气校准FMRI方法来响应视觉 健康的年轻和老年受试者的任务。在AIM 2中，我们将与校准fMRI并行执行FMRS 抑制性GABA和兴奋性谷氨酸的测量。在AIM 3中，我们将使用1H [13C] -MRS进行专门 在老化的视觉皮层中，测量神经元CMRO2（通过TCA循环）选择性降低。 与我们对视觉皮层（视觉皮层）激活大脑区域的变化的测试同时，我们还将执行 仅在后扣带回皮层（PCC）中进行相同的测量，这是主要的枢纽 默认模式网络（DMN）已显示在任务期间停用。休息状态的fMRI研究 衰老表明DMN连接发生了变化，但是没有研究查看其任务 使用定量fMRI或FMRS方法的响应。了解代谢和神经调节性 激活和停用区域之间的差异对于理解改变的基础至关重要 健康衰老的功能反应。拟议的工作具有很高的人类健康意义 理解衰老中神经元活动改变和验证A的基本机制 新型的多模式MRI/MRS生物标志物评估这些机制并有可能评估 尽管1H [13C] -MRS尚未广泛可用，但我们将 评估在校准fMRI确定的静止状态下神经元CMRO2是否提供了类似的结果。因为 校准的fMRI方法不需要气体吸入，它广泛适用于患者人群。