in Vivo Quantification of Cerebellar GABA and NAA in Essential Tremor

项目描述 尽管其发病率很高，但特发性震颤（ET）是研究最少和最差的疾病之一， 了解神经系统疾病。在最基本的生物学水平上，人们对其 基础病理解剖学和病理生理学。最近的尸检报告显示， 40%的浦肯野细胞（PC）的损失在ET，这表明在机械水平上，这种常见的 神经系统疾病可能是神经退行性疾病但验尸结果好坏参半。在 目前，ET领域的中心辩论围绕着一个问题，“PC丢失是一种 的特点”。不幸的是，迄今为止，对这一问题的处理仅限于 需要进行事后研究并采取新的方法。位于小脑皮层的PC是 大脑中γ-氨基丁酸（GABA）的主要仓库，将其GABA释放到大脑中。 小脑齿状核水平的突触间隙。因此，小脑齿状核GABA水平 是PC数量的方便的体内标记物。此外，N-乙酰天冬氨酸（NAA），一种氨基 在神经元的胞质溶胶中发现的酸是神经元完整性的方便的体内标记物。 小脑皮质拟议研究的长期目标是阐明 ET的潜在病理生理学。这个研究项目的目标是， 实现这一长期目标步骤是进行体内磁共振 磁共振波谱（MRS），以量化小脑齿状核中的GABA和小脑齿状核中的NAA水平。 小脑皮质在50例ET与50名对照，无论是横截面和纵向。的 这项研究的中心假设是， ET.我们计划透过以下方法，达致这项申请的整体目的 三个目标。目标1：在这个横断面神经影像学目标中，我们将使用基线MRS（年 1 - 2）评估体内小脑齿状GABA水平和小脑皮质NAA水平 (NAA/总肌酸（TCR）。目标2：在这个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，并以探索性的方式，齿状GABA水平，以确定是否有一个 在50例ET病例中，这些水平的纵向下降超过了这些水平的任何纵向下降。 50个对照组。目的3：我们将交叉验证体内MRS结果与死后 在50例ET病例中，有10 - 15例的脑组织学和生化结果，我们预计， 在5年的研究中死亡。我们希望拟议的研究将阐明潜在的 并提供有用的诊断生物标志物以及 用于未来的神经保护试验。

PROJECT DESCRIPTION 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.