Environmental Epidemiology of Essential Tremor

特发性震颤的环境流行病学

• 批准号: 9229079
• 负责人: ELAN D LOUIS
• 金额: $ 81.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229079
• 关键词: Address; Adherence; Biological Markers; Blood; Bradykinesia; Brain; Case-Control Studies; Clinical; Cohort Studies; Comorbidity; Complement; Complex; Consumption; Country; Development; Diet; Diet Modification; Disease; Environmental Epidemiology; Environmental Risk Factor; Epidemiologist; Essential Tremor; Etiology; Europe; Family history of; Family member; First Degree Relative; Genes; Genetic; Goals; Hematological Disease; Incidence Study; Individual; Indoles; Inherited; Intention Tremor; Investigation; Knowledge; Laboratory Animals; Lead; Link; Manganese; Meat; Mediterranean Diet; Metabolic; Metabolism; Nail plate; Neurologist; Neurotoxins; New York; North America; Organ; Organic solvent product; Parkinson Disease; Patients; Pesticides; Prospective cohort; Prospective cohort study; Publishing; Reproducibility; Research; Research Design; Risk; Risk Factors; Role; Sampling; Sampling Studies; Severities; Source; Spain; Spouses; Time; Tissue Sample; Tissues; Toxin; Tremor; base; case control; epidemiology study; follow-up; high risk; human tissue; interest; modifiable risk; prospective; public health relevance; pyridine; response; stem

 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.

 描述（由申请人提供）：我们的研究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，我们一直在研究几种环境神经毒素是否与 ET 相关。这些研究表明哈马烷 (HA)（1-甲基-9H-吡啶并[3,4-b]吲哚）和 ET 之间的联系，表明 ET 病例（尤其是家族性 ET）与对照受试者相比，血液和脑部 HA 浓度 ([HA]) 升高。 HA 是饮食中（尤其是肉类）中存在的一种神经毒素。给实验动物施用 HA 会产生类似于 ET 的严重震颤。然而，HA 和 ET 之间的联系尚未得到令人信服的证实。所有流行病学研究均为病例对照研究；因此，尚不清楚高血 [HA] 是否先于 ET 发生。该提案的目标 1 将解决这个问题。医管局的故事也变得更加复杂和多维。因此，我们最近感兴趣地发现，纽约帕金森病 (PD) 病例的血液 [HA] 高于对照组。 HA 的结构与 MPTP 相似，MPTP 是一种与 PD 密切相关的神经毒素。 ET和PD都是震颤疾病；一些患者同时患有两种疾病（ET+PD；即，他们同时患有这两种疾病）。 HA - PD 关联是否可重复，它是否追踪以震颤而非运动迟缓/强直为主要特征的 PD 亚型，以及来自血液的生物标志物发现是否也出现在 PD 的感兴趣的靶器官（即大脑）中，这些都值得关注。 不知道。该提案的目标 2 将解决这众多问题。最后，同时患有 ET 和 PD 的个体是否具有最高的血液 [HA] 尚不清楚。该提案的目标 3 将解决这个问题。为了弥补这些知识差距，在本申请中，我们提出了一项为期 5 年的研究，其中涉及 3 个相互关联的目标，利用几种类型的人体组织（血液、大脑）： 目标 1：通过研究基线血液 [HA] 与队列研究中发生 ET 事件之间的关联，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。目标 3：评估同时患有 ET 和 PD (ET+PD) 患者的血液 HA 水平。这将是唯一朝着这个方向进行的研究——探索疾病的病因学作用 ET 中的环境因素，更具体地说是毒素。因此，它将补充许多正在进行的寻找 ET 基因的研究。这项研究可能会明确确定第一个可改变的 ET 危险因素（即膳食 HA）。这也将是唯一一项评估这种毒素 HA（其结构与 MPTP 相似）在 PD 患者中可能的病因作用和组织浓度的研究。