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，比帕金森病的发病率高20倍。高达6%的总人口患有ET。无法控制的颤抖最终迫使10 - 25%的患者过早退休。目前还没有治愈的方法，也很少有药物可以减轻震颤，尽管深部脑刺激已经提供了有希望的结果。临床证据和神经影像学研究表明，小脑是中枢参与ET，临床和动物研究的证据表明，可能有一个干扰γ氨基丁酸（GABA）神经递质系统。虽然ET在临床上是进行性的，但对其潜在的病理学知之甚少。很少有出版的验尸报告。ET研究的基本问题是，是否可以根据特定脑区特定细胞类型的形态学或形态测量学变化来识别潜在的病理学？第二，ET是否存在神经递质异常，是细胞丢失的结果还是没有细胞丢失？这项拟议的研究将是一项合作努力，涉及美国和加拿大的四个中心，其中有24名ET患者的尸检组织档案。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的储存库，用于新的前瞻性收集的ET大脑，在五年期间收集36个额外的ET大脑。将60个ET大脑与40个对照大脑进行比较。主要目的1是研究ET的病理学，以确定是否有特定脑区的变化。使用常规形态学方法和定量形态测定评估（体视学），检查组织的变化，包括主要关注区域（小脑半球）和次要关注区域（红核、丘脑、下橄榄核）的细胞丢失。我们假设，在小脑的变化和细胞损失将在更大程度上存在于ET比对照组的大脑。主要目的二是研究GABA神经递质系统。我们推测，将有差异，小脑GABA能免疫标记ET相比，控制大脑。目前的ET疗法是偶然发现的，在高达50%的患者中无效。了解ET的病理变化和神经化学异常对设计治疗ET的新方法至关重要。

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.