Noninvasive Antioxidant Quantification in the Human Brain under Oxidative Stress

氧化应激下人脑的无创抗氧化剂定量

• 批准号: 8235551
• 负责人: Melissa J Terpstra
• 金额: $ 29.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235551
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; American; Antioxidants; Automatic Data Processing; Biochemistry; Biological Assay; Biological Markers; Brain; Brain region; Chemicals; Clinical; Computer software; Data; Dementia; Development; Elderly; Environment; Glutathione; Goals; Health; Homeostasis; Human; Imaging Device; Impaired cognition; Investigation; Investigational Therapies; Knowledge; Lead; Life; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Memory; Methods; Mission; Modeling; Neurodegenerative Disorders; Neurotransmitters; Occipital lobe; Outcome; Oxidative Stress; Pathologic Processes; Patients; Personal Satisfaction; Physicians; Prevention; Prevention strategy; Process; Quality of life; Relative (related person); Relaxation; Research; Research Personnel; Rest; Scientist; Staging; Technology; Testing; Thinking; Time; Translating; aging brain; ascorbate; cingulate cortex; cognitive function; computerized data processing; design; follow-up; improved; insight; instrumentation; nervous system disorder; neurochemistry; new technology; normal aging; novel; prevent; radiofrequency; response

DESCRIPTION (provided by applicant): The objective of this proposal is to advance the mission of improving the health and well-being of older Americans by augmenting ongoing dementia prevention and treatment initiatives. It undertakes research on dementia associated with both normal aging and AD. A new scientist will develop a novel and powerful human brain antioxidant assay using state-of-the art instrumentation. The approach will be translated to the clinical environment so that it can be disseminated for use with new research. Specifically, the concentrations of two important antioxidants, ascorbate (Asc) and glutathione (GSH) will be measured noninvasively in the human brain. One aim is to measure whether a recent finding of lower brain GSH concentration in the occipital cortex of cognitively normal elder subjects is also found in the posterior cingulate cortex, and whether human brain Asc homeostasis persists in both brain regions. A complementary specific aim is to determine whether lower brain GSH concentration also occurs under the oxidative stress associated with Alzheimer's disease (AD). At the same time, data measured in subjects with AD have potential to advance this powerful new technology toward discovering an early stage biomarker. A sub aim is to make this technology available to a wide range of physicians and investigators. As such, data processing will be fully automated using commercially available software. This novel noninvasive technology facilitates a paradigm shift from systemic assays to quantifying antioxidants directly in the affected brain region. The approach will take advantage of state of the art 7 T instrumentation while developing analogous methods on a clinical 3 T scanner. The process of optimizing magnetic resonance spectroscopy (MRS) for quantification of brain Asc and GSH concentrations necessitated reliable quantification of an extensive neurochemical profile (i.e. 19 brain metabolites), which includes the four compounds that are typically observed. Spectra acquired in stimulated echo acquisition mode (STEAM) will be de-convolved quantitatively into contributions from the metabolites that contribute discernable resonances using a linear combination model approach (LCModel). Reliable quantification of brain GSH and Asc concentrations will first be achieved using ultra high field MRS with multiple transmit coil technology and accompanying radiofrequency (B1) shimming, then translated to a lower field clinical platform. Successful completion will determine whether low brain glutathione concentration is widespread in the elder human brain and whether this difference is exacerbated by AD. PUBLIC HEALTH RELEVANCE: Antioxidants are important for having a good memory and for smart thinking when people get old, and that is important for everyone's quality of life. This research will find out if normal aging and Alzheimer's disease use up brain antioxidants. It will develop a new imaging tool that can help doctors to stop cognitive decline.

描述（由申请人提供）：该提案的目的是通过扩大正在进行的预防痴呆症和治疗计划来提高美国老年人健康和福祉的使命。它进行了与正常衰老和AD相关的痴呆症的研究。一位新科学家将使用最先进的仪器开发一种新颖而强大的人脑抗氧化测定法。该方法将转化为临床环境，以便可以将其传播以与新研究一起使用。具体而言，将在人脑中无创测量两种重要的抗氧化剂（ASC）和谷胱甘肽（GSH）的浓度。一个目的是衡量最近发现，在后扣带回皮层中还发现了认知正常的老年受试者枕皮层中较低的脑GSH浓度，以及在两个大脑区域的人脑ASC稳态是否仍然存在。互补的特定目的是确定在与阿尔茨海默氏病（AD）相关的氧化应激下是否也发生了较低的脑GSH浓度。同时，在患有AD的受试者中测量的数据有可能推进这项强大的新技术，以发现早期生物标志物。一个次的目的是使这项技术可用于广泛的医师和研究人员。因此，数据处理将使用市售软件完全自动化。这种新型的无创技术促进了从系统性测定到直接量化受影响大脑区域的抗氧化剂的范式转变。该方法将在临床3 T扫描仪上开发类似方法的同时，利用最新的7 T仪器。优化磁共振光谱（MRS）来定量脑ASC和GSH浓度的过程需要对广泛的神经化学谱（即19个脑代谢产物）进行可靠的定量，其中包括通常观察到的四种化合物。在刺激回声采集模式（Steam）中获取的光谱将被定量地撤销到来自代谢物的贡献中，这些代谢物使用线性组合模型方法（LCModel）贡献了可辨别的共振。首先，使用具有多个发射线圈技术和随附的射频（B1）的超高场MRS来实现脑GSH和ASC浓度的可靠定量，然后转换为较低的场临床平台。成功的完成将确定低脑谷胱甘肽浓度在人类大脑中是否普遍存在，并且AD是否会加剧这种差异。 公共卫生相关性：抗氧化剂对于拥有良好的记忆和当人们变老时的明智思维非常重要，这对每个人的生活质量很重要。这项研究将找出正常的衰老和阿尔茨海默氏病消耗脑抗氧化剂。它将开发一种新的成像工具，可以帮助医生停止认知能力下降。