Pathogenesis Of Essential Tremor: Cerebellar Metabolism

特发性震颤的发病机制：小脑代谢

• 批准号: 7109212
• 负责人: ELAN D LOUIS
• 金额: $ 46.26万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7109212
• 关键词: basal ganglia; brain metabolism; brain morphology; cerebellar Purkinje cell; cerebellum; clinical research; gamma aminobutyrate; gliosis; glutamates; human tissue; immunocytochemistry; morphometry; neuromuscular disorder; neuropathology; olivary body; postmortem; thalamus; tissue resource /registry; tremor

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.

描述（由申请人提供）：特发性震颤 (ET) 是最常见的震颤疾病，其患病率是帕金森病的二十倍。高达 6% 的总人口患有 ET。无法控制的颤抖最终迫使 10 - 25% 的患者提前退休。尽管深部脑刺激已提供了有希望的结果，但目前尚无治愈方法，也很少有药物可以减轻震颤。临床证据和神经影像学研究表明，小脑主要参与 ET，临床和动物研究的证据表明，γ 氨基丁酸 (GABA) 神经递质系统可能存在紊乱。虽然 ET 在临床上是进展性的，但对其潜在病理学知之甚少。尸检结果很少发表。 ET 研究的基本问题是，是否可以根据特定大脑区域中特定细胞类型的形态或形态测量变化来识别潜在的病理学？其次，ET 是否存在神经递质异常，无论是由于细胞丢失还是在没有细胞丢失的情况下导致的？拟议的研究将是一项涉及美国和加拿大四个中心的合作项目，这些中心提供了 24 名 ET 患者的尸检档案。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，用于存放新的前瞻性收集的外星人大脑，在五年内额外收集 36 个外星人大脑。 60 个 ET 大脑将与 40 个对照大脑进行比较。主要目标 1 是研究 ET 的病理学，以确定特定大脑区域是否存在变化。使用传统的形态学方法和定量形态测量评估（体视学），将检查组织的主要感兴趣区域（小脑半球）和次要感兴趣区域（红核、丘脑、下橄榄核）的变化，包括细胞损失。我们假设，与对照大脑相比，ET 中小脑的变化和细胞损失会更大程度地出现。主要目标 2 是研究 GABA 神经递质系统。我们假设，与对照大脑相比，ET 中的小脑 GABA 能免疫标记存在差异。目前的 ET 疗法是偶然出现的，但对高达 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 新疗法至关重要。