Environmental Epidemiology of Essential Tremor

描述（由申请人提供）：特发性震颤（ET）是人类最常见的震颤原因，但其病因尚不清楚。环境毒物可能是其病因之一。这些因素被认为在其他神经退行性疾病中发挥重要作用，但它们在ET中的作用受到的关注较少。在过去的八年中（2000 - 2008），我们研究了几种假定的毒物。在寻找ET的环境风险因素中，Harmane（1-甲基- 9h -吡啶[3,4-b]吲哚）是最有希望的早期候选者。在过去的三年中（2005 - 2008），我们研究了纽约临床ET病例样本中可能导致血液中Harmane浓度升高的几种潜在机制。这些研究表明饮食因素可能起作用。在这些研究的同时，我们继续在纽约收集血液样本。展望未来，我们的目标是明确建立这种神经毒素与ET之间的联系。这是一个为期五年的竞争性更新，我们建议解决四个相互关联的问题。首先，虽然在ET病例中观察到血液中有害毒素浓度升高，但尚未对这种神经毒素的脑浓度进行调查。ET是一种脑部疾病，大脑被认为是这种神经毒素的目标器官。ET脑中的有害物质浓度是否升高（特异性目标1）？其次，我们的发现来源于一项主要来自纽约一家三级转诊中心的ET病例研究。如果要对一组以完全不同的方式（即以社区为基础）在世界各地确定的ET病例进行抽样，是否会发现血液中有害物质浓度升高（具体目标2）？第三，我们发现的升高的有害物质浓度是横断面观察，在一个时间点采样血液。目前尚不清楚，如果几年后在第二个时间点重新评估，这些相同的ET病例是否会持续显示血中有害物质浓度升高（具体目标3）？最后，一项研究发现帕金森病患者血中有害物质浓度升高，这就提出了一个问题，即血液有害物质升高是否与ET特异性相关，还是仅仅是一种更普遍的神经系统疾病的全球标志（Specific Aim 4）？大约50%的ET病例是非家族性的。鉴于其在40岁至40岁人群中的患病率为4.0%，那么40岁至40岁人群中有2.0%的人患有非家族性ET，然而这种震颤的环境基础才刚刚开始探索。识别和了解这些有毒物质是预防这种治疗方案很少的进行性神经系统疾病的第一步。公共卫生相关性：我们估计，年龄在50 - 40岁之间的人口中有2.0%患有散发性（即非家族性）特发性震颤（ET），然而这种震颤的环境基础才刚刚开始探索。在寻找ET的环境风险因素方面，Harmane（1-甲基- 9h -吡啶[3,4-b]吲哚）是最有希望的早期候选药物。这是一项为期五年的竞争性更新，我们建议牢固地建立这种神经毒素与ET之间的联系。

DESCRIPTION (provided by applicant): Essential tremor (ET) is the most common cause of tremor in humans yet its etiology remains unclear. Environmental toxicants are likely to contribute to its etiology. Such factors are thought to play an important role in other neuro-degenerative diseases, but their role in ET has received less attention. During the last eight years (2000 - 2008), we have studied several putative toxicants. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is the most promising early candidate in the search for environmental risk factors for ET. During the past three years (2005 - 2008), we studied several potential mechanisms that could underlie elevated blood harmane concentrations in our clinic-based sample of ET cases in New York. These studies suggest that dietary factors might play a role. In tandem with these studies, we have continued to collect blood harmane samples in New York. Moving forward, our goal is to now definitely establish the links between this neurotoxin and ET. This is a five-year competitive renewal in which we propose to address four inter-related questions. First, although elevated harmane concentrations have been observed in ET cases in blood, brain concentrations of this neurotoxin have not been investigated. ET is a brain disease and the brain is the presumed target organ of this neurotoxin. Are harmane concentrations elevated in the ET brain (Specific Aim 1)? Second, our finding was derived from a single study of ET cases primarily from one tertiary referral center in New York. If one were to sample a group of ET cases ascertained in a completely different manner (i.e., community-based) half-way around the world, would one find an elevated blood harmane concentration (Specific Aim 2)? Third, our finding of an elevated harmane concentration was a cross-sectional observation, sampling blood at a single time point. It is not clear whether these same ET cases would persist in demonstrating elevated blood harmane concentrations if re-assessed at a second time point several years later (Specific Aim 3)? Finally, one study found elevated blood harmane concentrations in Parkinson's disease, raising the question as to whether elevated blood harmane is specifically linked with ET or is merely a more general, global marker of neurological illness (Specific Aim 4)? Approximately 50% of ET cases are non-familial. Given its population prevalence of 4.0% in persons age > 40 years, then 2.0% of the population aged > 40 years has a non-familial form of ET, yet the environmental underpinnings for this tremor are just beginning to be explored. Identification and understanding of these toxicants is the first step in preventing a progressive neurological disease with few treatment options. PUBLIC HEALTH RELEVANCE: We estimate that 2.0% of the population aged > 40 years has sporadic (i.e., non-familial) essential tremor (ET), yet the environmental underpinnings for this tremor are just beginning to be explored. Harmane (1-methyl-9H- pyrido[3,4-b]indole) is the most promising early candidate in the search for environmental risk factors for ET. This is a five-year competitive renewal in which we propose to firmly establish the links between this neurotoxin and ET.