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.

项目概要/摘要 人类的健康衰老与认知、记忆和处理效率的下降有关2。 解释功能改变的主要理论是衰老的线粒体理论，其中线粒体丧失 提供足够能量以支持功能和改变 GABA/谷氨酸神经调节的能力。 校准功能 MRI (fMRI) 的最新发展允许对神经元的变化进行直接成像 令人惊讶的是，任务引起的氧化代谢变化（ΔCMRO2）的测量结果显示， 发现尽管衰老过程中 CMRO2 基线较低，但神经激活却有所增加。 我们建议通过使用校准的 fMRI、功能 1H-MRS 的新颖组合来解决这一悖论 (fMRS) 和 1H[13C]-MRS 方法直接测试线粒体衰老和神经调节在 我们的一般假设是：（i）健康时功能反应的增加是矛盾的。 主要在感觉区域观察到的衰老是对较低基线 CMRO2 的补偿，但这还不够 获得与年轻受试者相同的神经功能能量支持（线粒体衰老理论）； (ii) 在年轻人中建立的 GABA 浓度与 BOLD 激活之间的反比关系 受试者在老年人中迟钝（神经调节理论）我们将通过三个具体目标来检验这些假设。 在目标 1 中，我们将使用一种新颖的无气体校准 fMRI 方法来测量 ΔCMRO2 以响应视觉 在目标 2 中，我们将与校准的 fMRI、fMRS 并行执行。 在目标 3 中，我们将使用 1H[13C]-MRS 来具体测量抑制性 GABA 和兴奋性谷氨酸。 测量神经元 CMRO2（通过 TCA 循环），我们发现它在衰老的视觉皮层中选择性减少。 在测试视觉皮层等激活的大脑区域的变化的同时，我们还将执行 在后扣带皮层 (PCC) 中同时进行相同的测量，这是大脑的主要枢纽 默认模式网络（DMN）已被证明在任务中的静息态功能磁共振成像研究中会停用。 衰老表明 DMN 连接发生了改变，但还没有研究关注其任务 使用定量 fMRI 或 fMRS 方法了解代谢和神经调节的反应。 激活区域和失活区域之间的差异对于理解激活区域的基础至关重要 所提出的工作对健康老龄化具有很高的潜在人类健康意义。 用于了解衰老过程中神经活动变化背后的基本机制并验证 新型多模态 MRI/MRS 生物标志物用于评估这些机制并可能评估 尽管 1H[13C]-MRS 尚未广泛应用，但我们将会对机制靶向治疗产生反应。 评估根据校准的功能磁共振成像确定的静息神经 CMRO2 是否提供类似的结果。 校准后的功能磁共振成像方法不需要吸入气体，广泛适用于患者人群。