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，这种疾病通常是进行性的。虽然它比帕金森氏症流行20倍，但在我们最初申请的时候(2002年)，我们注意到只有15例尸检，其中大部分来自前现代时代。因此，对ET的基本病理几乎一无所知。尽管经常重申ET‘没有病理’，但这并不是基于严格的研究。自2003年以来，我们的目标一直是建立Essential Tremor中央脑库，以解决ET研究中的一个基本问题：根据特定脑区的形态变化能否识别潜在的病理？在对51个ET脑和34个对照脑进行密集收集和研究后，我们发现，ET脑中确实存在可识别的病理变化：82.3%的ET脑有小脑退行性变化，表现为鱼雷数量增加和浦肯野细胞(PC)数量轻微减少，而17.7%的ET有脑干路易体。因此，在这一点上，我们已经描述了ET大脑的几个基本变化。这两种经病理证实的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。具体目的1是通过对PC神经元形态的详细研究，加深我们对小脑ET(Aim 1A)和路易体ET(Aim 1B)患者死后变化的认识。在目标1A中，我们还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个区域，我们将扩大我们的范围，以包括小脑的其他每个功能解剖区域(目标1C)。在Aim 1D中，我们将把我们的分析扩展到丘脑。具体目的2是建立临床特征和死后脑变化(临床-病理相关性)之间的基本联系。在我们2002年的应用中，通过设计，临床评估是简短和间接的(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，其中44例我们预计在这个五年计划期间死亡。通过这样做，我们可以开始确定具有两种病理亚型ET患者的特定临床特征。我们的目标是通过：(1)增加我们对ET的病理解剖的理解，以及(2)在医生在活着的患者身上观察到的东西与我们在详细的尸检研究中发现的东西之间建立必要的联系，以推动这一领域的发展。与公共卫生相关的特发性震颤(ET)是最常见的神经系统疾病之一，但直到最近才有很少的尸检研究。在过去的5年里，我们对51个ET脑和34个对照脑进行了密集的收集和研究，发现ET脑确实存在可识别的病理变化。我们在这一竞争性更新应用中的目的是通过更详细的浦肯野细胞的定量形态研究(目标1)来促进我们对ET死后变化的了解，并建立临床特征和死后脑变化之间的基本联系(目标2)。我们的基于组织的研究将使我们处于一个独特的位置，开始解决关于ET的基本机制问题，并可能允许治疗医生在一生中预测患者可能患有哪种亚型的ET。

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.