Environmental Epidemiology of Essential Tremor

 描述(申请人提供)：我们的研究致力于研究震颤的原因，特别是最常见的震颤类型--特发性震颤(ET)。自2000年以来，我们一直在研究几种环境神经毒素是否与ET有关。这些研究表明，Harmane(HA)(1-甲基-9H-吡啶并[3，4-b]吲哚)与ET之间存在联系，表明ET患者血液和脑内HA浓度([HA])升高。家族性ET)与对照组比较。HA是一种存在于饮食中的神经毒素(特别是在肉中)。给实验动物注射HA会产生类似于ET的剧烈动作震颤。然而，HA和ET之间的联系尚未令人信服地建立起来。所有的流行病学研究都是病例对照研究；因此，尚不清楚高血[HA]是否先于ET的发病。该提案的目标1将解决这一问题。房委会的故事也变得更加复杂和多维。因此，我们最近很感兴趣地发现，在纽约，帕金森病(PD)患者的血液[HA]高于对照组。HA在结构上与MPTP相似，MPTP是一种与帕金森病密切相关的神经毒素。ET和PD都是震颤障碍；一些患者同时患有这两种疾病(ET PD；也就是说，他们是这两种情况的共病)。HA-PD的联系是否可重现，它是否跟踪帕金森病的亚型，其中震颤而不是运动迟缓/僵直是主要特征，以及血液中的生物标志物发现是否也出现在帕金森病的感兴趣的靶器官(即大脑)中。 不知道。这项提案的目标2将解决这无数的问题。最后，同时患有ET和PD的个体是否具有最高的血[HA]尚不清楚。本提案的目标3将解决这一问题。为了弥合这些知识上的差距，在本申请中，我们提出了一项为期5年的研究，该研究有3个相互关联的目标，利用几种类型的人类组织(血液，脑)：目标1：通过在队列研究中研究基线血液[HA]与事件ET的发展之间的联系，确定HA和ET之间的联系。目标2：通过将我们的观察扩展到另一个国家(西班牙)，进一步巩固HA和PD之间正在出现的联系。目的：评价ET合并PD(ET PD)患者血透明质酸(HA)水平。这将是唯一朝这个方向发展的研究方向--探索肺炎的病因学作用 环境因素，更具体地说，是ET中的毒素。因此，它将补充许多正在进行的寻找ET基因的研究。这项研究可能导致明确ET的第一个可修改的危险因素(即饮食HA)。这也将是唯一一项评估这种毒素HA的可能病因作用和组织浓度的研究，这种毒素在结构上与MPTP相似，在PD患者中。

 DESCRIPTION (provided by applicant): Our research is devoted to studying the causes of tremor, and especially essential tremor (ET), which is the most common type of tremor. Since 2000, we have been investigating whether several environmental neurotoxins are associated with ET. A link between harmane (HA) (1- methyl-9H-pyrido[3,4-b]indole) and ET has been emerging from these studies, which show that blood and brain HA concentration ([HA]) is elevated in ET cases (esp. familial ET) vs. control subjects. HA is a neurotoxin present in the diet (esp. in meat). Administration of HA to laboratory animals produces severe action tremor resembling ET. Yet the link between HA and ET has not been convincingly established. All epidemiological studies have been case-control studies; thus, it is not clear whether high blood [HA] precedes the onset of ET. Aim 1 of this proposal will address this issue. The HA story has also become more complex and multi-dimensional. Thus, we were recently intrigued to find that blood [HA] was higher in Parkinson's disease (PD) cases than controls in New York. HA is structurally similar to MPTP, a neurotoxin closely linked with PD. ET and PD are both tremor disorders; some patients develop both disorders (ET+PD; i.e., they are comorbid for the two conditions). Whether the HA - PD link is reproducible, whether it tracks with the subtype of PD in which tremor rather than bradykinesia/rigidity is the predominant feature, and whether biomarker findings from blood also occur in the target organ of interest (i.e., the brain) in PD is not known. Aim 2 of this proposal will address this myriad of issues. Finally, whether individuals who are comorbid for both ET and PD have the highest blood [HA] is not known. Aim 3 of this proposal will address this issue. To close these gaps in knowledge, in this application, we propose a 5-year study with 3 inter-related aims that draw on several types of human tissue (blood, brain): AIM 1: To nail down the links between HA and ET by studying the association between baseline blood [HA] and the development of incident ET in a cohort study. AIM 2: To further solidify the emerging links between HA and PD by extending our observations to another country (Spain). AIM 3: To assess blood levels of HA in patients who have both ET and PD (ET+PD). This would be the only study heading in this direction - exploring the etiological role of environmental factors, and more specifically toxins, in ET. It would thus complement the many ongoing studies searching for ET genes. The study could lead to the clear identification of the first modifiable risk factor for ET (i.e., dietary HA).This would also be the only study assessing the possible etiological role and tissue concentrations of this toxin, HA, which is structurally similar to MPTP, in patients with PD.