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的活性是阐明正常和解散神经元的基础功能，具有谷氨酸（GLU）和γ-氨基丁酸（GABA）是大脑的主要兴奋性和抑制性神经递质。这种理解在自闭症谱系障碍（ASD）中尤其重要，这是一套神经发育障碍的特征是社会交流中持续缺陷和受限制的缺陷重复和刻板印象的行为模式。尽管表现和严重程度有所不同，但ASD发生在所有种族和社会经济群体都有终生的持续时间，并影响68名儿童中有1个美国。不幸的是，这些疾病的病因尚未完全理解，这种技术开发新型非侵入性成像工具来研究ASD脑神经化学生物标志物是对NIH PA 10-158“自闭症谱系障碍研究”的回应。创新是根据该项目进行的评估将不仅有助于调查ASD，还可以帮助其他神经精神病学和需要高级成像技术的神经发育障碍。尽管ASD具有异质性，但患者可能具有最终的常见生化途径，并有可能具有对类似治疗的反应，现在假设ASD是由于兴奋性和抑制性神经递质。被称为“ E/I平衡”理论，两种动物的发现模型和人类建议ASD的特征是由于关键大脑区域的高度启动性 GLU和/或GABA减少。而这种神经化学失衡的体内证据开始通过使用J编辑的1H磁共振光谱来出现（Mega-Press是电流选择的方法）强大的体内测量是耗时的和有问题的。 GLU测量是直接，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（MMS）重叠靶向的GABA信号，占检测到的信号的40-60％，领导研究人员将结果数据称为GABA+MMS或仅仅是GABA+。 MRS检测的MM是还报道了暴露的区域变化，正常受试者的变异性以及对两个年龄的依赖性和病理。即使对于单素研究，先前提出的MM抑制技术也不会被广泛使用，对B0磁场变化的时间耗时或高度敏感。该建议旨在通过系统的设计，实施和测试来克服这些限制可抑制MM的J编辑的单Voxel（目标1和2）和多素序列（AIM 3）序列以测量这些有针对性的神经化学物质，从多个大脑区域产生时间效率的测量。这些新工具将用于评估被诊断为ASD的青春期患者的神经化学失衡（AIM 4）。