Reliability and regional specificity of glutathione and gamma-aminobutyric acid edited magnetic resonance spectroscopy in the human subcortex

人类皮层下谷胱甘肽和γ-氨基丁酸编辑磁共振波谱的可靠性和区域特异性

• 批准号: 10434510
• 负责人: Ian Greenhouse
• 金额: $ 7.38万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434510
• 关键词: Adult; Affect; Anatomy; Animal Model; Animals; Antioxidants; Area; Autopsy; Basal Ganglia; Benchmarking; Biological Testing; Bradykinesia; Brain; Brain imaging; Brain region; Cells; Cessation of life; Chemicals; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Data; Data Set; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dopamine; Elderly; Evaluation; Exhibits; Foundations; Future; Glutathione; Goals; Human; Image; Imaging Techniques; Individual; Intervention; Investigation; Left; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Methods; Motor; Motor Cortex; Motor output; Movement; Movement Disorders; Muscle; Muscle Rigidity; Neurologist; Neurotransmitters; Output; Oxidative Stress; Oxygen; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Persons; Physiologic pulse; Population; Prevention; Procedures; Process Measure; Protocols documentation; Research; Risk; Scanning; Severities; Side; Source; Specificity; Structure; Substantia nigra structure; Symptoms; System; Techniques; Technology; Testing; Thalamic structure; Time; Tissue Model; Translations; Treatment Efficacy; Tremor; Vendor; Work; brain cell; brain tissue; cell injury; chemical reaction; clinical diagnosis; clinical investigation; experience; experimental study; gamma-Aminobutyric Acid; human tissue; imaging modality; imaging platform; in vivo; interest; meetings; motor symptom; neurochemistry; neuroimaging; neuroimaging marker; non-invasive imaging; novel; pre-clinical; routine care; tool

PROJECT SUMMARY A biological test to diagnose, track, and predict Parkinson’s disease (PD) remains elusive. Development of such a test will aid the detection, treatment, and possible prevention of PD. Novel applications of neuroimaging technologies for anatomically localized measurements of specific brain chemicals show promise in meeting this need. Our proposed work will adapt a recently developed magnetic resonance imaging technique to measure chemicals in deep brain structures in vivo. This work aims to evaluate the reliability and regional specificity of this technique in healthy adult humans and will selectively measure chemicals in target brain areas implicated in PD. Establishing measurement reliability and anatomical specificity is an important prerequisite for the future use of the protocol in clinical research and will lay the foundation for studies aimed at developing this approach as a neuroimaging biomarker of PD to aid in clinical diagnosis, disease tracking, and evaluation of treatment efficacy. The loss of dopamine in the basal ganglia is a defining feature of PD. However, abnormal levels of other brain chemicals may precede the loss of dopamine and accelerate PD progression. These chemicals include glutathione (GSH) and gamma-aminobutyric acid (GABA). GSH is a naturally occurring antioxidant that protects brain cells from oxidative stress which results from chemical reactions with unstable oxygen-containing molecules. GSH neutralizes these unstable molecules. Insufficient levels of GSH hasten dopamine cell loss in animal models of PD and are also observed in post-mortem deep brain tissue from individuals with PD. GABA is another naturally occurring chemical and is the principle inhibitory neurotransmitter in the adult human brain. GABA levels in deep brain structures of individuals with PD correlate with motor symptom severity. In vivo measurement of GSH and GABA in targeted deep brain regions could have far reaching impacts by helping to predict whether a person will develop PD, track disease progression, and assess treatment efficacy. Single-voxel magnetic resonance spectroscopy (MRS) is a non-invasive imaging method for quantifying the amounts of specific molecules within targeted anatomical regions of interest. A specialized MRS sequence was recently developed for the simultaneous measurement of GSH and GABA in the human brain, but has not been used to study deep brain areas commonly affected in PD. The proposed work will apply this MRS scan in the substantia nigra and thalamus, two regions that exhibit abnormal GSH and GABA levels in PD. Thirty healthy adults will undergo MRS scanning twice, on separate days. At each session, simultaneous measurements of GSH and GABA will be taken in three regions of interest: 1) the substantia nigra on both sides of the brain, 2) the left thalamus, and 3) the right thalamus. Each scanning session will take approximately 60 minutes. Comparisons across days will evaluate reliability and comparisons between regions will assess regional specificity. The data will provide benchmarks for future translation of the method to PD clinical trials. Immediate next steps for this work will focus on the development of the imaging protocol as a diagnostic and preclinical tool.

项目摘要 诊断，跟踪和预测帕金森氏病（PD）的生物学测试仍然难以捉摸。 这种测试的开发将有助于检测，治疗和可能预防PD。小说 神经影像技术在解剖学上的特定测量中的应用 大脑化学物质在满足这一需求方面表现出希望。我们建议的工作将适应最近 开发的磁共振成像技术可在深脑结构中测量化学物质 体内。这项工作旨在评估该技术在健康方面的可靠性和区域特异性 成年人，将有选择地测量PD实施的目标脑区域的化学物质。 建立测量可靠性和解剖学特异性是重要的先决条件 该方案在临床研究中的未来使用，并将为针对的研究奠定基础 将这种方法作为PD的神经成像生物标志物，以帮助临床诊断，疾病 跟踪和评估治疗效率。 基底神经节中多巴胺的丧失是PD的定义特征。但是，异常 其他大脑化学物质的水平可能是多巴胺丧失并加速PD进展。 这些化学物质包括谷胱甘肽（GSH）和γ-氨基丁酸（GABA）。 GSH是一个 天然存在的抗氧化剂可保护脑细胞免受氧化应激，这是由 与不稳定的含氧分子的化学反应。 GSH中和这些不稳定 分子。 GSH的水平不足促进PD动物模型中的多巴胺细胞损失，并且是 还观察到来自PD个体的验尸深脑组织。加巴是另一个 天然化学物质，是成年人的原理抑制性神经递质 脑。 PD个体深脑结构中的GABA水平与运动症状相关 严重程度。目标深脑区域中GSH和GABA的体内测量可能具有远 通过帮助预测一个人是否会发展PD，跟踪疾病来达到影响 进展和评估治疗效率。 单素磁共振光谱（MRS）是一种非侵入性成像方法 量化目标解剖区域内特定分子的量。一个 最近开发了专门的MRS序列，以简单地测量GSH 和人脑中的GABA，但尚未用于研究深度大脑区域 在PD中受到影响。拟议的工作将在尼格拉和塔拉姆斯的田间扫描中应用 PD中暴露了异常GSH和GABA水平的两个区域。 在不同的日子里，有30名健康的成年人将进行两次扫描太太。在每个会话中， 在三个感兴趣的区域将同时进行GSH和GABA的同时测量：1） 大脑两侧的黑质，2）左丘脑和3）右丘脑。每个 扫描课程大约需要60分钟。跨天的比较将评估 区域之间的可靠性和比较将评估区域特异性。数据将提供 将方法转换为PD临床试验的将来翻译的基准。立即下一步 工作将集中于成像协议作为诊断和临床前工具的开发。