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
基本信息
- 批准号:10647162
- 负责人:
- 金额:$ 65.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
Dewan Syed Fahmeed...的其他基金
Acquisition of a Bruker 11.7T/16cm Preclinical Scanner for Novel MRI/MRSI Studies
采购布鲁克 11.7T/16cm 临床前扫描仪用于新型 MRI/MRSI 研究
- 批准号:1063051110630511
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Interleaved 1H/23Na imaging for invasive and proliferative phenotypes of brain tumors
用于脑肿瘤侵袭性和增殖表型的交错 1H/23Na 成像
- 批准号:1063426910634269
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Hypoxia and pH Responsive Nanoparticles for Targeted Drug Delivery to Ischemic Stroke
用于缺血性中风靶向药物输送的缺氧和 pH 响应纳米颗粒
- 批准号:1068184610681846
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Delayed white matter loss in concussive head injuries and its treatment
颅脑震荡迟发性脑白质丢失及其治疗
- 批准号:1053280010532800
- 财政年份:2021
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Delayed white matter loss in concussive head injuries and its treatment
颅脑震荡迟发性脑白质丢失及其治疗
- 批准号:1035446910354469
- 财政年份:2021
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
MRS validation of computational metabolic modeling of human brain function to determine energetic disruptions underlying fMRI-derived functional connectivity in degenerative or psychiatric disorders
MRS 验证人脑功能的计算代谢模型,以确定退行性或精神疾病中 fMRI 衍生的功能连接潜在的能量破坏
- 批准号:92460039246003
- 财政年份:2017
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Multivalent PARACEST agents for quantitative molecular imaging
用于定量分子成像的多价 PARACEST 试剂
- 批准号:84701668470166
- 财政年份:2010
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Translation of smart contrast agents for brain tumor characterization by MR
MR 脑肿瘤表征智能造影剂的转化
- 批准号:84087928408792
- 财政年份:2010
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Multivalent PARACEST agents for quantitative molecular imaging
用于定量分子成像的多价 PARACEST 试剂
- 批准号:81011718101171
- 财政年份:2010
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Multivalent PARACEST agents for quantitative molecular imaging
用于定量分子成像的多价 PARACEST 试剂
- 批准号:82815398281539
- 财政年份:2010
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
相似国自然基金
TBX20在致盲性老化相关疾病年龄相关性黄斑变性中的作用和机制研究
- 批准号:82220108016
- 批准年份:2022
- 资助金额:252 万元
- 项目类别:国际(地区)合作与交流项目
LncRNA ALB调控LC3B活化及自噬在体外再生晶状体老化及年龄相关性白内障发病中的作用及机制研究
- 批准号:81800806
- 批准年份:2018
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
APE1调控晶状体上皮细胞老化在年龄相关性白内障发病中的作用及机制研究
- 批准号:81700824
- 批准年份:2017
- 资助金额:19.0 万元
- 项目类别:青年科学基金项目
KDM4A调控平滑肌细胞自噬在年龄相关性血管老化中的作用及机制
- 批准号:81670269
- 批准年份:2016
- 资助金额:55.0 万元
- 项目类别:面上项目
老年人一体化编码的认知神经机制探索与干预研究:一种减少与老化相关的联结记忆缺陷的新途径
- 批准号:31470998
- 批准年份:2014
- 资助金额:87.0 万元
- 项目类别:面上项目
相似海外基金
The Proactive and Reactive Neuromechanics of Instability in Aging and Dementia with Lewy Bodies
衰老和路易体痴呆中不稳定的主动和反应神经力学
- 批准号:1074953910749539
- 财政年份:2024
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Fluency from Flesh to Filament: Collation, Representation, and Analysis of Multi-Scale Neuroimaging data to Characterize and Diagnose Alzheimer's Disease
从肉体到细丝的流畅性:多尺度神经影像数据的整理、表示和分析,以表征和诊断阿尔茨海默病
- 批准号:1046225710462257
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Core D: Integrated Computational Analysis Core
核心D:综合计算分析核心
- 批准号:1055589610555896
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
The contribution of air pollution to racial and ethnic disparities in Alzheimer’s disease and related dementias: An application of causal inference methods
空气污染对阿尔茨海默病和相关痴呆症的种族和民族差异的影响:因果推理方法的应用
- 批准号:1064260710642607
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别:
Effects of Aging on Neuronal Lysosomal Damage Responses Driven by CMT2B-linked Rab7
衰老对 CMT2B 相关 Rab7 驱动的神经元溶酶体损伤反应的影响
- 批准号:1067878910678789
- 财政年份:2023
- 资助金额:$ 65.69万$ 65.69万
- 项目类别: