in Vivo Quantification of Cerebellar GABA and NAA in Essential Tremor

特发性震颤中小脑 GABA 和 NAA 的体内定量

• 批准号: 8734499
• 负责人: ELAN D LOUIS
• 金额: $ 62.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734499
• 关键词: Address; Age; Amino Acids; Anatomy; Autopsy; Biochemical; Biological; Biological Markers; Brain; Brain region; Cell Count; Cerebellar cortex structure; Cerebellum; Cessation of life; Clinical; Creatine; Cytosol; Dentate nucleus; Development; Diagnostic; Disease; Disease Progression; Essential Tremor; Functional disorder; Future; Goals; High Prevalence; Magnetic Resonance Spectroscopy; Measurement; Measures; Metric; N-acetylaspartate; Nature; Nerve Degeneration; Neurons; Pathologic; Population; Proteins; Publishing; Purkinje Cells; Reporting; Research; Research Project Grants; Severities; Swelling; Synaptic Cleft; Time; Tremor; burnout; calbindin; case control; end stage disease; gamma-Aminobutyric Acid; illness length; in vivo; magnetic resonance spectroscopic imaging; nervous system disorder; neuroimaging; neuronal cell body; next generation; novel; public health relevance; repository

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.

描述（由申请人提供）：尽管特发性震颤（ET）患病率很高，但它是研究最少、了解最少的神经系统疾病之一。在最基本的生物学水平上，对其基本的病理解剖学和病理生理学知之甚少。最近的尸检研究报告了ET中浦肯野细胞（PC）的30 - 40%损失，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的。但验尸结果好坏参半。目前，ET领域的中心辩论围绕着这样一个问题：“PC丢失是ET的一个特征吗？”不幸的是，迄今为止对这一问题的处理仅限于事后研究，因此需要一种新的处理方法。小脑皮质中的PC是大脑γ-氨基丁酸（GABA）的主要仓库，将其GABA释放到小脑齿状核水平的突触间隙中。因此，小脑齿状核GABA水平是PC数量的一个方便的体内标志物。此外，N-乙酰天冬氨酸（NAA），在神经元的胞质溶胶中发现的氨基酸，是一个方便的小脑皮质神经元完整性的体内标记。拟议研究的长期目标是阐明ET的基础病理生理学的基本性质。本研究项目的目的，这是实现这一长期目标的下一步，是进行体内磁共振波谱（MRS），以量化水平的GABA在小脑齿状和NAA在小脑皮质在50 ET情况下与50对照组，无论是横截面和纵向。这项研究的中心假设是， 在ET中逐步破坏PC。我们计划通过追求以下三个目标来实现本申请的总体目标。目标1：在这个横断面神经影像学的目标，我们将使用MRS在基线（1 - 2年），以评估在体内小脑齿状GABA水平和小脑皮质NAA水平（NAA/总肌酸，TCR）在ET病例和对照。目标二：在这个纵向神经影像学的目标，我们将进行第二次MRS研究（4 - 5年），以评估在体内小脑皮质NAA/TCR水平，并在探索性的方式，齿状GABA水平，以确定是否有一个纵向下降，这些水平在50例ET超过任何纵向下降，这些水平在50个对照组。目标三：我们将交叉验证在体内MRS结果与死后的组织学和生化结果在50例ET的情况下，我们预计在5年的研究期间死亡的10 - 15的大脑。我们希望这项研究能够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以及疾病进展的标志物。