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Robust 1H MRSI of GABA, Glutamate, Glutamine, and Glutathione

GABA、谷氨酸、谷氨酰胺和谷胱甘肽的稳定 1H MRSI

基本信息

批准号：
9910230
负责人：
Daniel M Spielman
金额：
$ 42.02万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910230
关键词：
Adolescent Affect Age Animal Model Anterior Antioxidants Architecture Area Auditory area Autopsy Behavior Biochemical Pathway Biological Markers Brain Brain Diseases Brain region Characteristics Child Clinical Clinical Research Companions Consumption Data Data Set Dependence Development Diagnosis Disease Equilibrium Etiology Evaluation Exhibits Frequencies Functional disorder Future Gender Generations Genetic Glutamates Glutamine Glutathione Goals Grant Heterogeneity Human Imaging Device Imaging Techniques Individual Investigation Light Magnetic Resonance Spectroscopy Maps Measurement Measures Methods Monitor Motor Cortex Neurobiology Neurodevelopmental Disorder Neurons Neuropsychological Tests Neurotransmitters Obsessive compulsive behavior Pathology Patients Pattern Physiologic pulse Procedures Protons Psychopathology Publishing Reporting Research Research Personnel Resolution Scanning Severities Side Signal Transduction Slice Social Interaction Stereotyping Structure-Activity Relationship Techniques Testing Therapeutic Intervention Time United States United States National Institutes of Health Variant Visual Cortex adolescent patient auditory thalamus autism spectrum disorder base brain abnormalities brain metabolism cognitive ability data acquisition design gamma-Aminobutyric Acid imaging modality imaging study in vivo in vivo magnetic resonance spectroscopy innovation insight interest macromolecule magnetic field magnetic resonance spectroscopic imaging neurochemistry neurodevelopment neuroimaging neuropsychiatric disorder neurotransmitter antagonist non-invasive imaging novel novel strategies patient population response social communication socioeconomics temporal measurement theories tool

项目摘要

Project Abstract Understanding neurotransmitter activity is fundamental to elucidating normal and diseased neuronal function, with glutamate (Glu) and γ-aminobutyric acid (GABA) being the brain's primary excitatory and inhibitory neurotransmitters. Such understanding is particularly critical in autism spectrum disorder (ASD), a set of neurodevelopment disorders characterized by persistent deficits in social communication and restricted, repetitive, and stereotyped patterns of behavior. Although varying in presentation and severity, ASD occurs in all ethnic and socioeconomic groups, has a lifelong duration, and affects an estimated 1 out of 68 children in the United States. Unfortunately, the etiologies of these disorders are not fully understood, and this technical development proposal to develop novel non-invasive imaging tools for studying ASD brain neurochemical biomarkers is in response to NIH PA 10-158 “Research on Autism Spectrum Disorders”. The innovations to be evaluated under this project will help not only investigating ASD, but also other neuropsychiatric and neurodevelopmental disorders where advanced imaging techniques are needed. Despite the heterogeneity of ASD, patients may share final common biochemical pathways and potentially be responsive to similar treatments, and ASD is now hypothesized to result from an imbalance between excitatory and inhibitory neurotransmitters. Known as the “E/I balance” theory, findings from both animal models and humans suggest ASD is characterized by hyper-excitability in critical brain regions due to increased Glu and/or decreased GABA. While in vivo evidence of such neurochemical imbalances is beginning to emerge through the use of J-edited 1H magnetic resonance spectroscopy (MEGA-PRESS being the current method of choice) robust in vivo measurements are time-consuming and problematic. Glu measurement is straightforward, but separation from closely related glutamine (Gln) is difficult. Furthermore, co-edited macromolecules (MMs) overlap the targeted GABA signal and account for 40-60% of the detected signal, leading investigators to refer to the resulting data as GABA+MMs or simply GABA+. MRS-detected MMs are also reported to exhibit regional variations, variability across normal subjects, and dependence on both age and pathology. Even for single-voxel studies, prior proposed MM-suppression techniques are not widely used, being either time-consuming or highly sensitive to B0 magnetic field variations. This proposal seeks to overcome these limitations via the systematic design, implementation, and testing of robust MM-suppressed J-edited single-voxel (Aims 1 and 2) and multi-voxel (Aim 3) sequences to measure these targeted neurochemicals, yielding time-efficient measurements from multiple brain regions. These new tools will be used to assess neurochemical imbalances in adolescent patients diagnosed with ASD (Aim 4).

项目摘要了解神经递质活动是阐明正常和患病神经元的基础谷氨酸 (Glu) 和 γ-氨基丁酸 (GABA) 是大脑的主要兴奋剂和抑制性神经递质。这种理解对于自闭症谱系障碍 (ASD) 尤为重要，这是一种神经发育障碍的特征是社交沟通持续缺陷和受限，重复的、刻板的行为模式。尽管自闭症谱系障碍 (ASD) 的表现和严重程度各不相同，但所有种族和社会经济群体，都会持续一生，并影响估计每 68 名儿童中的 1 名美国。不幸的是，这些疾病的病因尚未完全了解，并且这种技术开发新型非侵入性成像工具用于研究 ASD 脑神经化学物质的开发提案生物标志物是对 NIH PA 10-158“自闭症谱系障碍研究”的回应。待创新的内容该项目下的评估不仅有助于调查自闭症谱系障碍，还有助于其他神经精神和需要先进成像技术的神经发育障碍。尽管自闭症谱系障碍存在异质性，但患者可能具有最终共同的生化途径，并且有可能对类似的治疗有反应，现在假设自闭症谱系障碍是由于两者之间的不平衡造成的兴奋性和抑制性神经递质。被称为“E/I 平衡”理论，来自两种动物的研究结果模型和人类表明自闭症谱系障碍的特点是关键大脑区域过度兴奋，这是由于 Glu 增加和/或 GABA 减少。虽然这种神经化学失衡的体内证据已经开始通过使用 J 编辑的 1H 磁共振波谱（MEGA-PRESS 是当前的选择的方法）稳健的体内测量既耗时又存在问题。谷氨酸测量值是简单，但与密切相关的谷氨酰胺 (Gln) 分离很困难。此外，共同编辑大分子 (MM) 与目标 GABA 信号重叠，占检测到的信号的 40-60%，导致研究人员将所得数据称为 GABA+MM 或简称 GABA+。 MRS 检测到的 MM 是据报告还表现出区域差异、正常受试者之间的差异以及对年龄的依赖性和病理学。即使对于单体素研究，先前提出的 MM 抑制技术也没有广泛使用，要么耗时，要么对 B0 磁场变化高度敏感。该提案旨在通过系统设计、实施和测试来克服这些限制稳健的 MM 抑制 J 编辑的单体素（目标 1 和 2）和多体素（目标 3）序列进行测量这些有针对性的神经化学物质，可以对多个大脑区域进行高效的测量。这些新工具将用于评估诊断为 ASD 的青少年患者的神经化学失衡（目标 4）。