Environmental Epidemiology of Essential Tremor

 描述（由申请人提供）：我们的研究计划致力于研究震颤的原因，特别是特发性震颤（ET），这是最常见的震颤类型。自2000年以来（R 01 NS 039422），我们已经调查了几种环境神经毒素是否与ET相关。这些研究表明，与对照组相比，ET病例（尤其是家族性ET）的血和脑中HA浓度（[HA]）升高，表明HA（1-甲基-9H-吡啶并[3，4-B]吲哚）与ET之间存在联系。HA是一种存在于饮食中的神经毒素（特别是肉类）。对实验室动物施用HA产生类似ET的严重动作性震颤。然而，医管局与环境影响评估之间的关系，至今仍未能令人信服地确立。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发作。本提案的目标1将解决这一问题。医管局的故事也变得更加复杂和多层面。因此，在当前的资助期内，我们发现在纽约，帕金森病（PD）患者的血液[HA]高于对照组。HA在结构上类似于MPTP，MPTP是一种与PD密切相关的神经毒素。ET和PD都是震颤病症;一些患者发展两种病症（ET+PD;即，他们是两种疾病的共病者）。HA-PD关联是否是可再现的，其是否追踪其中震颤而不是运动迟缓/僵硬是主要特征的PD亚型，以及来自血液的生物标志物发现是否也发生在感兴趣的靶器官中（即，PD中的脑）是未知的。本提案的目标2将解决这一系列问题。最后，ET和PD共病的个体是否具有最高的血液[HA]尚不清楚。目标3将解决这个问题。为了弥补这些知识差距，在这一竞争性继续申请中，我们提出了一项为期5年的研究，其中有3个相互关联的目的，这些目的利用了几种类型的人体组织（血液、脑）：目的1：通过研究队列研究中基线血液[HA]与事件ET发展之间的关联，确定HA与ET之间的联系。目的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之间的新兴联系。目的3：探讨内皮素（ET）和帕金森病（PD）患者血透明质酸（HA）水平的变化。这是唯一一项朝着这个方向发展的研究--探索环境因素，特别是莫伊毒素在ET中的病因作用。因此，它将补充许多正在进行的寻找ET基因的研究。该研究可能会明确识别ET的第一个可改变的风险因素（即，这也是唯一评估这种毒素HA在PD患者中可能的病因学作用和组织浓度的研究，这种毒素HA在结构上类似于MPTP。

 DESCRIPTION (provided by applicant): Our research program is devoted to studying the causes of tremor, and especially essential tremor (ET), which is the most common type of tremor. Since 2000 (R01 NS039422), we have investigated 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, in the current funding period, we were 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 will address this issue. To close these gaps in knowledge, in this competing continuation 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 is the only study that is heading in this direction - exploring the etiological role of environmental factors, and moe 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 is also the only study that is assessing the possible etiological role and tissue concentrations of this toxin, HA, which is structurally similar to MPTP, in patients with PD.