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

项目摘要 诊断、跟踪和预测帕金森病（PD）的生物学测试仍然难以捉摸。 开发这样的测试将有助于PD的检测，治疗和可能的预防。小说 神经成像技术在解剖学定位测量特定 大脑中的化学物质有望满足这一需求。我们建议的工作将适应最近 开发了磁共振成像技术来测量大脑深层结构中的化学物质 in vivo.这项工作的目的是评估的可靠性和区域特异性，这项技术在健康 成年人，并将选择性地测量涉及PD的目标大脑区域中的化学物质。 建立测量可靠性和解剖特异性是测量的重要前提。 未来在临床研究中使用该方案，并将为旨在 开发这种方法作为PD的神经成像生物标志物，以帮助临床诊断，疾病 跟踪和评价治疗效果。 基底神经节中多巴胺的丢失是PD的定义特征。然而， 其他脑化学物质的水平可能先于多巴胺的损失并加速PD进展。 这些化学物质包括谷胱甘肽（GSH）和γ-氨基丁酸（GABA）。GSH是一种 天然存在的抗氧化剂，保护脑细胞免受氧化应激， 与不稳定的含氧分子发生化学反应。GSH中和了这些不稳定的 分子。在PD动物模型中，GSH水平不足加速多巴胺细胞损失， 在PD患者的死后脑深部组织中也观察到了这种现象。GABA是另一种 是一种天然存在的化学物质，是成年人的主要抑制性神经递质 个脑袋帕金森病患者脑深部GABA水平与运动症状的关系 严重性。在体内测量目标脑深部区域的GSH和GABA可能有很大的意义。 通过帮助预测一个人是否会发展为PD，跟踪疾病， 进展，并评估治疗效果。 单体素磁共振波谱（MRS）是一种非侵入性成像方法， 量化感兴趣的靶向解剖区域内的特定分子的量。一 最近开发了一种专门的MRS序列，用于同时测量GSH 和GABA在人脑中的作用，但还没有被用于研究脑深部区域 PD的影响。拟议的工作将在黑质和丘脑中应用这种MRS扫描， 这两个区域在PD中表现出异常的GSH和GABA水平。 30名健康成年人将在不同的日子接受两次MRS扫描。在每届会议上， GSH和GABA的同时测量将在三个感兴趣的区域进行：1） 大脑两侧的黑质，2）左丘脑，和3）右丘脑。每个 扫描过程大约需要60分钟。跨天比较将评估 区域间的可靠性和比较将评估区域的特殊性。数据将提供 为将来将该方法转化为PD临床试验提供基准。立即为此采取的后续步骤 工作重点将是开发成像协议，作为诊断和临床前工具。

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.