Environmental Epidemiology of Essential Tremor

描述(申请人提供)：特发性震颤(ET)是人类震颤最常见的原因，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着重要作用，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年)，我们研究了几种假定的毒物。Harmane(1-甲基-9H-吡啶并[3，4-b]吲哚)是寻找ET环境风险因素的最有希望的早期候选者。在过去的三年中(2005-2008)，我们研究了几种潜在的机制，这些机制可能是导致纽约ET病例的临床样本中血液中HARM浓度升高的原因。这些研究表明，饮食因素可能起到了一定作用。在这些研究的同时，我们继续在纽约采集血液样本。展望未来，我们的目标是现在明确地建立这种神经毒素和ET之间的联系。这是一次为期五年的竞争延期，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的Harmane浓度升高，但这种神经毒素的脑浓度尚未被调查。ET是一种脑部疾病，大脑是这种神经毒素的假定靶器官。在ET脑中Harmane浓度是否升高(特定目标1)？其次，我们的发现来自于主要来自纽约一个三级转诊中心的一项关于ET病例的单一研究。如果在半个世界以完全不同的方式(即，以社区为基础)确定的一组ET病例进行抽样，会不会发现血液中的有害物质浓度升高(具体目标2)？第三，我们发现哈曼浓度升高是一项横断面观察，在单个时间点采集血液样本。如果在几年后的第二个时间点重新评估这些相同的ET病例(具体目标3)，是否会持续显示出血液中HARM浓度升高，尚不清楚。最后，一项研究发现，帕金森氏症患者血液中Harmane浓度升高，这引发了这样一个问题：血液Harmane浓度升高是否与ET有特定联系，还是仅仅是神经疾病的一个更普遍的、全球标记物(特定目标4)？大约50%的ET病例是非家族性的。鉴于其40岁人群中4.0%的患病率，那么2.0%的40岁人群患有非家族性ET，然而这场地震的环境基础才刚刚开始探索。识别和了解这些毒物是在几乎没有治疗选择的情况下预防进行性神经疾病的第一步。与公共卫生相关：我们估计，40岁的人群中有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。Harmane(1-甲基-9H-吡啶并[3，4-b]吲哚)是寻找ET环境风险因素的最有希望的早期候选者。这是一项为期五年的竞争更新，在此期间，我们建议牢固地建立这种神经毒素和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.