Pathogenesis of Essential Tremor: Cerebellar Metabolism

描述（申请人提供）：特发性震颤（ET）是最常见的神经系统疾病之一，但也是研究最少的疾病之一。很少有药物治疗这种疾病，它通常是渐进的。虽然它的发病率是帕金森病的20倍，但在我们最初申请（2002年）时，我们注意到只有15例尸检，其中大多数来自前现代时代。因此，对ET的潜在病理几乎一无所知。尽管经常重申ET“无病理”，但这并非基于严谨的研究。自2003年以来，我们的目标是建立特发性震颤集中脑存储库，以解决ET研究中的一个基本问题：是否可以根据特定脑区域的形态学变化确定潜在病理？在对51个ET脑和34个对照脑进行集中收集和研究后，我们发现ET脑确实存在可识别的病理改变：82.3%的ET脑存在小脑退行性改变，表现为水雷数量增加和浦肯野细胞（“小脑ET”）数量轻度减少，而17.7%的ET脑存在脑干路易体。因此，在这一点上，我们已经描述了ET大脑的几个基本变化。两种病理鉴定的ET亚型之间的临床差异尚未得到很好的研究。我们现在希望超越我们最初的工作。特异性目的1是通过对PC神经元形态的详细研究，提高我们对小脑ET （AIM 1A）和路易体ET （AIM 1B）患者死后变化的认识。在Aim 1A中，我们也将开始研究神经丝蛋白。由于我们之前的分析仅限于一个小脑半球的单一区域，我们将扩大我们的范围，包括小脑的其他功能解剖区域（Aim 1C）。在Aim 1D中，我们将把我们的分析扩展到丘脑。SPECIFIC AIM 2是建立临床特征与死后脑变化（临床病理相关性）之间的基本联系。在我们2002年的申请中，临床评估被设计为简短和间接的（电话和录像带）。现在我们的目标是对175例老年ET病例进行全面的面对面临床评估，我们预计其中44人将在这五年的建议中死亡。通过这样做，我们可以开始确定两种ET病理亚型患者的具体临床特征。我们的目标是通过以下方式推进这一领域：(1)增加我们对ET病理解剖的理解，(2)在医生对活着的患者的观察和我们在详细的死后研究中发现的东西之间建立必要的联系。特发性震颤（ET）是最常见的神经系统疾病之一，但直到最近才有很少的死后研究。在过去的5年里，我们集中收集和研究了51个ET脑和34个对照脑，发现ET脑确实存在可识别的病理变化。我们在这个竞争性更新应用程序中的目标是通过对浦肯野细胞进行更详细的定量形态学研究来提高我们对ET死后变化的认识（目的1），并建立临床特征与死后大脑变化之间的基本联系（目的2）。我们以组织为基础的研究将使我们处于一个独特的位置，开始解决有关ET的基本机制问题，并可能使治疗医生预测患者一生中可能患有哪种ET亚型。

DESCRIPTION (provided by applicant): Essential tremor (ET) is one of the most common neurological diseases yet it is also among the least studied. Few medications treat the disorder, which is usually progressive. Although it is as much as twenty times more prevalent than Parkinson's disease, at the time of our original application (2002), we noted that there were only 15 postmortems, most of which were from the pre-modern era. Hence, there was almost no knowledge of the underlying pathology of ET. Although often reiterated that 'there is no pathology' in ET, this was not based on rigorous study. Since 2003, our goal has been to establish the Essential Tremor Centralized Brain Repository to address a fundamental question in ET research: can an underlying pathology be identified in terms of morphological changes in specific brain regions? After intensively collecting and then studying 51 ET brains and 34 control brains, we have discovered that, indeed, there are identifiable pathological changes in the ET brain: 82.3% of ET brains have cerebellar degenerative changes in the form of increased numbers of torpedoes and mild reduction in Purkinje cell (PC) number ("cerebellar ET") whereas 17.7% have brainstem Lewy bodies. Hence, at this point, we have described several basic changes in the ET brain. Clinical differences between the two pathologically-identified subtypes of ET have not been well studied. We now wish to move beyond our initial work. SPECIFIC AIM 1 is to advance our knowledge of the postmortem changes in patients with cerebellar ET (Aim 1A) and Lewy body ET (Aim 1B) through detailed studies of PC neuronal morphology. In Aim 1A, we will also begin to study neurofilament proteins. Because our previous analyses were confined to a single region of one cerebellar hemisphere, we will broaden our scope to include each of the other functional-anatomic regions of the cerebellum (Aim 1C). In Aim 1D, we will extend our analyses to the thalamus. SPECIFIC AIM 2 is to establish basic links between clinical features and postmortem brain changes (clinical-pathological correlation). The clinical evaluation in our 2002 application was, by design, brief and indirect (telephone and videotape). Now our aim is to conduct a comprehensive in- person clinical evaluation of 175 elderly ET cases, 44 of whom we expect to die during this five year proposal. In doing so, we can begin to identify the specific clinical features that characterize patients with each of the two pathological subtypes of ET. Our goal is to advance this field by: (1) increasing our understanding of the pathological anatomy of ET, and (2) forging the needed links between what physicians observe in living patients and what we uncover in detailed postmortem studies. PUBLIC HEALTH RELEVANCE Essential tremor (ET) is among the most common neurological diseases, yet until recently there had been very few postmortem studies. After intensively collecting and studying 51 ET brains and 34 control brains over the past 5 years, we have discovered that, indeed, there are identifiable pathological changes in the ET brain. Our aims in this competitive renewal application are to advance our knowledge of the postmortem changes in ET with more detailed quantitative morphological studies of Purkinje cells (Aim 1) and to establish basic links between clinical features and postmortem brain changes (Aim 2). Our tissue-based research will place us in unique a position to begin to address basic mechanistic questions about ET and may allow treating physicians to predict during life which subtype of ET a patient is likely to have.