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: 8613863
• 负责人: ELAN D LOUIS
• 金额: $ 66.84万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613863
• 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

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.

项目描述 尽管特发性震颤（ET）的患病率很高，但它却是研究最少、研究最差的疾病之一。 了解神经系统疾病。在最基本的生物学层面上，人们对其知之甚少。 基础病理解剖学和病理生理学。最近的尸检研究报告称 30 - ET 中浦肯野细胞 (PC) 损失 40%，这表明在机制层面上，这种常见现象 神经系统疾病可能是神经退行性疾病。但事后调查结果好坏参半。在 目前，ET 领域的中心争论围绕着这样一个问题：“PC 丢失是否会导致 ET 的特征？不幸的是，迄今为止解决这个问题的方法仅限于 需要事后研究和新的方法。 PC 位于小脑皮层，是 大脑γ-氨基丁酸（GABA）的主要仓库，将GABA释放到大脑中 小脑齿状核水平的突触裂。因此，小脑齿状 GABA 水平 是一种方便的体内PC编号标记。此外，N-乙酰天冬氨酸（NAA）是一种氨基 神经元细胞质中发现的酸，是神经元完整性的一种方便的体内标记物 小脑皮质。拟议研究的长期目标是阐明基本性质 ET 的基本病理生理学。该研究项目的目标是下一个 实现这一长期目标的一步是进行体内磁共振 光谱 (MRS) 来量化小脑齿状中的 GABA 和大脑中的 NAA 水平 50 个 ET 病例与 50 个对照组的小脑皮层的横截面和纵向比较。这 拟议研究的中心假设是，PC 正在逐渐遭到破坏。 等。我们计划通过追求以下目标来实现此应用程序的总体目标 三个目标。目标 1：在这个横断面神经影像学目标中，我们将在基线（年 1 - 2) 评估体内小脑齿状 GABA 水平和小脑皮质 NAA 水平 ET 病例和对照中的（NAA/总肌酸，tCR）。目标 2：在这个纵向神经影像目标中， 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，以确定是否存在 50 个 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 个控制级别。目标 3：我们将交叉验证体内 MRS 结果与尸检结果 我们预计 50 例 ET 病例中 10 - 15 例的大脑组织学和生化结果 5年研究期间死亡。我们期望拟议的研究将阐明潜在的 疾病病理生理学并提供有用的诊断生物标志物以及疾病标志物 未来神经保护试验的疾病进展。