in Vivo Quantification of Cerebellar GABA and NAA in Essential Tremor

描述(由申请人提供)：尽管其发病率很高，但原发性震颤(ET)是研究最少、了解最少的神经系统疾病之一。在最基本的生物学水平上，人们对其潜在的病理解剖学和病理生理学知之甚少。最近的尸检研究表明，ET中的浦肯野细胞(PC)丢失了30%-40%，这表明从机制上讲，这种常见的神经系统疾病可能是神经退行性疾病。但尸检结果好坏参半。目前，ET领域的中心辩论围绕着这样一个问题：“个人电脑丢失是ET的一个特征吗？”不幸的是，到目前为止，对这个问题的处理方法仅限于尸检研究，需要一种新的方法。位于小脑皮质的PC是大脑伽马氨基丁酸(GABA)的主要储存库，将它们的GABA释放到小脑齿状核水平的突触裂隙中。因此，小脑齿状回GABA水平是一种方便的体内PC数标志物。此外，N-乙酰天冬氨酸(NAA)是一种发现于神经元胞浆中的氨基酸，是小脑皮质神经元完整性的一个方便的体内标记物。这项拟议研究的长期目标是阐明ET潜在病理生理学的基本性质。这项研究项目的目标，也是实现这一长期目标的下一步，是进行体内磁共振波谱(MRS)，以量化50例ET患者和50名对照小脑皮质的GABA和NAA水平，包括横断面和纵向。这项拟议研究的中心假设是，有一个 逐步销毁ET中的PC。我们计划通过实现以下三个目标来实现此应用程序的总体目标。目的1：在这个横断面的神经成像目标中，我们将使用基线(1-2年)的MRS来评估ET患者和对照组的小脑齿状回GABA水平和小脑皮质NAA水平(NAA/总肌酸，TCR)。目的：在这一纵向神经成像目标中，我们将进行第二次MRS研究(第4-5年)，以评估体内小脑皮质NAA/TCR水平，并以探索性方式测定GABA水平，以确定50例ET患者的这些水平是否存在纵向下降，超过50名对照组这些水平的纵向下降。目的3：我们将对50例ET患者中10-15例的体内MRS结果与死后组织学和生化结果进行交叉验证，我们预计这些患者将在5年的研究中死亡。我们期望这项拟议的研究将阐明潜在的疾病病理生理学，并为未来的神经保护试验提供有用的诊断生物标志物和疾病进展的标志物。

DESCRIPTION (provided by applicant): Despite its high prevalence, essential tremor (ET) it is among the least-studied and most poorly- understood neurological diseases. On the most basic biological level, little is known about its underlying pathologic-anatomy and pathophysiology. Recent postmortem studies report a 30 - 40% loss of Purkinje cells (PCs) in ET, suggesting that on a mechanistic level, this common neurological disease could be neurodegenerative. But postmortem results have been mixed. At the moment, the central debate in the ET field revolves around the question, "is PC loss a feature of ET"? Unfortunately, the approach to this question has thus far been limited to postmortem studies and a fresh approach is needed. PCs, in the cerebellar cortex, are the major storehouse of brain gamma-aminobutyric acid (GABA), releasing their GABA into the synaptic cleft at the level of the cerebellar dentate nucleus. Thus, cerebellar dentate GABA level is a convenient in vivo marker of PC number. Furthermore, N-acetylaspartate (NAA), an amino acid found in the cytosol of neurons, is a convenient in vivo marker of neuronal integrity in the cerebellar cortex. The long-term goal of the proposed research is to elucidate the basic nature of the underlying pathophysiology of ET. The objective of this research project, which is the next step toward attainment of this long-term goal, is to perform in-vivo magnetic resonance spectroscopy (MRS) to quantify levels of GABA in the cerebellar dentate and NAA in the cerebellar cortex in 50 ET cases vs. 50 controls, both cross-sectionally and longitudinally. The central hypothesis for the proposed research is that there is a progressive destruction of PCs in ET. We plan to accomplish the overall objective of this application by pursuing the following three aims. Aim 1: In this cross-sectional neuroimaging aim, we will use MRS at baseline (Years 1 - 2) to assess in vivo cerebellar dentate GABA levels and cerebellar cortex NAA levels (NAA/total creatine, tCR) in ET cases and controls. Aim 2: In this longitudinal neuroimaging aim, we will perform a second MRS study (Years 4 - 5) to assess in vivo cerebellar cortex NAA/tCR levels and, in an exploratory manner, dentate GABA levels, to determine whether there is a longitudinal decline in these levels in 50 ET cases in excess of any longitudinal decline in these levels in 50 controls. Aim 3: We will cross validate the in vivo MRS findings with postmortem histological and biochemical findings in the brains of 10 - 15 of 50 ET cases whom we expect to die during the 5 year study. We expect that the proposed research will elucidate the underlying disease pathophysiology and provide useful diagnostic biomarkers as well as markers of disease progression for future neuroprotective trials.