Pathogenesis Of Essential Tremor: Cerebellar Metabolism

描述（由申请人提供）：特发性震颤（ET）是最常见的震颤障碍，比帕金森氏病患病率高20倍。高达6%的普通人群患有ET。无法控制的颤抖最终迫使10 - 25%的患者过早退休。这种病无法治愈，而且很少有药物能减轻震颤，尽管深部脑刺激提供了令人鼓舞的结果。临床证据和神经影像学研究表明，小脑中枢参与ET，临床和动物研究的证据表明，伽马氨基丁酸（GABA）神经递质系统可能存在干扰。虽然ET在临床上是进行性的，但对其潜在病理知之甚少。很少有公开的尸检报告。ET研究的基本问题是，是否可以根据特定脑区域特定细胞类型的形态学或形态计量学变化来确定潜在的病理？其次，ET中是否存在神经递质异常，无论是由于细胞丢失还是没有细胞丢失？这项拟议的研究将由美国和加拿大的四个中心合作进行，这些中心有24名ET患者的死后组织档案。此外，在国际特发性震颤基金会的帮助下，我们将在哥伦比亚大学建立一个集中存储库，用于收集新的ET大脑，在五年内再收集36个ET大脑。60个ET大脑将与40个对照组大脑进行比较。主要目的1是研究ET的病理，以确定特定脑区是否有改变。使用常规形态学方法和定量形态计量学评估（立体学），将检查主要感兴趣区域（小脑半球）和次要感兴趣区域（红核、丘脑、下橄榄核）的组织变化，包括细胞损失。我们假设ET中小脑的变化和细胞损失比对照大脑更严重。主要目的二是研究GABA神经递质系统。我们假设ET中的小脑gaba能免疫标记与对照脑相比存在差异。目前治疗ET的方法是偶然发现的，对高达50%的患者无效。了解ET的病理变化和神经化学异常对于设计ET的新疗法至关重要。

DESCRIPTION (provided by applicant): Essential tremor (ET) is the most common tremor disorder, twenty times more prevalent than Parkinson's disease. Up to 6% of the general population has ET. Uncontrollable trembling eventually forces 10 - 25% of patients to retire prematurely. There is no cure, and few medications lessen the tremor, although deep brain stimulation has provided promising results. Clinical evidence and neuro-imaging studies suggest that the cerebellum is centrally involved in ET, and evidence from clinical and animal studies suggests that there may be a disturbance in the gamma amino butyric acid (GABA) neurotransmitter system. While ET is clinically progressive, little is known about its underlying pathology. There have been few published postmortem examinations. The fundamental question in ET research is whether an underlying pathology can be identified in terms of morphological or morphometric changes of specific cell types in specific brain regions? Second, is there a neurotransmitter abnormality in ET, either resulting as a consequence of cell loss or in the absence of cell loss? The proposed study will be a collaborative effort involving four centers in the United States and Canada where archival postmortem tissue on 24 ET patients is available. In addition, with the help of the International Essential Tremor Foundation, we will establish at Columbia University a centralized repository for new prospectively-collected ET brains, collecting 36 additional ET brains during the five-year period. The 60 ET brains will be compared with 40 control brains. Primary Aim 1 is to study the pathology of ET to determine whether there are changes in specific brain regions. Using conventional morphological methods and quantitative morphometric assessments (stereology), tissue will be examined for changes, including cell loss, in the main region of interest (cerebellar hemispheres) and in secondary regions of interest (red nuclei, thalami, inferior olivary nuclei). We hypothesize that changes and cell loss in the cerebellum will be present to a greater extent in ET than in control brains. Primary Aim 2 is to study the GABA neurotransmitter system. We hypothesize that there will be differences in cerebellar GABA-ergic immuno-labeling in ET compared to control brains. Current therapies for ET have come to us by serendipity and are ineffective in up to 50% of patients. Knowledge of the pathological changes and neurochemical abnormality in ET is critical for the design of new therapies for ET.