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

项目总结 诊断、跟踪和预测帕金森氏病(PD)的生物测试仍然难以实现。 这种测试的发展将有助于帕金森病的检测、治疗和可能的预防。小说 神经成像技术在特定部位解剖定位测量中的应用 大脑化学物质在满足这一需求方面表现出了希望。我们提议的工作将改编成最近的一部 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 在活体内。这项工作旨在评估这项技术在健康人群中的可靠性和区域特异性。 并将选择性地测量与帕金森病有关的目标大脑区域的化学物质。 建立测量的可靠性和解剖学特异度是 未来该方案在临床研究中的应用，并将为旨在 发展这一方法作为帕金森病的神经影像生物标志物，以辅助临床诊断、疾病 跟踪和评估治疗效果。 基底节多巴胺的丧失是帕金森病的一个重要特征。然而，异常 其他大脑化学物质的水平可能先于多巴胺的丧失，并加速帕金森病的进展。 这些化学物质包括谷胱甘肽(GSH)和γ-氨基丁酸(GABA)。谷胱甘肽是一种 天然抗氧化剂，保护脑细胞免受因 与不稳定的含氧分子发生化学反应。GSH中和这些不稳定的 分子。GSH水平不足加速PD和ARE动物模型中多巴胺细胞的丢失 在帕金森病患者的死后深部脑组织中也观察到了这种情况。GABA是另一个 天然存在的化学物质，是成人体内主要的抑制性神经递质 大脑。帕金森病患者脑深部结构中GABA水平与运动症状的相关性 严肃性。靶向深部脑区GSH和GABA的活体测量可能有很大的影响 通过帮助预测一个人是否会患上帕金森病、跟踪疾病来达到影响 进展，并评估治疗效果。 单体素磁共振波谱(MRS)是一种非侵入性的成像方法 量化目标解剖感兴趣区域内特定分子的数量。一个 最近开发了专门的MRS序列，用于同时测量GSH 以及人类大脑中的GABA，但通常不被用于研究大脑深层区域 在帕金森州受影响。这项拟议的工作将在黑质和丘脑应用MRS扫描， 帕金森病患者GSH和GABA水平异常的两个区域。 30名健康成年人将在不同的日子接受两次MRS扫描。在每次会议上， 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)左侧丘脑，3)右侧丘脑。每个人 扫描会话大约需要60分钟。跨天的比较将评估 可靠性和地区间的比较将评估地区的特殊性。数据将提供 未来将该方法转化为PD临床试验的基准。紧随其后的下一步行动 工作重点将集中在开发成像方案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.