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.

项目总结/摘要 人类健康老龄化与认知、记忆和处理效率的下降有关。两 解释功能改变的主要理论是线粒体衰老理论，其中线粒体失去了 提供足够能量以支持功能和改变的GABA/谷氨酸神经调节的能力。 最近的发展，校准功能磁共振成像（fMRI）允许直接成像的变化，神经元， 活动在老化。令人惊讶的是，测量任务引起的氧化代谢变化（Δ CMRO 2）， 发现增加的神经元活化，尽管在老化中较低的基线CMRO 2。 我们建议解决这个矛盾，通过使用一种新的组合校准的功能磁共振成像，功能1H-MRS （fMRS）和1H[13 C]-MRS方法来直接测试线粒体老化和神经调节在脑缺血中的作用。 健康老龄化我们的一般假设是：（i）健康人的反常增加的功能反应， 主要在感觉区域观察到的衰老是对较低基线CMRO 2的补偿，但这还不够 实现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）; 和（ii）GABA浓度和BOLD激活之间的反比关系建立在年轻的 受试者在老年人中变钝（神经调节理论）。我们将以三个具体目标来检验这些假设。 在目标1中，我们将使用一种新的无气体校准的fMRI方法来测量Δ CMRO 2对视觉刺激的响应。 在健康的年轻人和老年人的任务。在目标2中，我们将与校准的fMRI并行执行fMRS 抑制性GABA和兴奋性谷氨酸的测量。在目标3中，我们将使用1H[13 C]-MRS来特异性地 测量神经元CMRO 2（通过TCA循环），我们发现它在老化的视觉皮层中选择性降低。 在测试大脑激活区域（如视觉皮层）变化的同时，我们还将进行 在后扣带皮层（PCC）中同时进行相同的测量，这是大脑皮层的主要中枢。 默认模式网络（DMN），已被证明在任务期间停用。静息态fMRI研究 衰老已经表明DMN的连接性发生了改变，但还没有研究观察它的任务。 使用定量fMRI或fMRS方法。了解代谢和神经调节 激活和失活区域之间的差异对于理解改变的基础至关重要。 健康老龄化的功能反应。这项工作具有很高的潜在人类健康意义， 为了理解衰老过程中神经元活动变化背后的基本机制， 一种新的多模态MRI/MRS生物标志物，用于评估这些机制并可能评估 对机制靶向治疗的反应。虽然1H[13 C]-MRS尚未广泛应用，但我们将 评估从校准的fMRI确定的静息神经元CMRO 2是否提供类似的结果。因为 校准的fMRI方法不需要气体吸入，它广泛适用于患者群体。