Pathogenesis of Essential Tremor: Cerebellar Metabolism

原发性震颤(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。一些 药物治疗这种疾病通常是进行性的。尽管它的流行程度比 帕金森？S病，在我们最初申请的时候(2002年)，我们注意到只有15例尸检，大多数 它们来自前现代时代。因此，对ET的基本病理几乎一无所知。虽然 经常重申，没有病理吗？在ET中，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来确定潜在的病理？在密集收集之后 然后研究了46个ET大脑和32个对照大脑，我们发现确实存在可识别的病理 ET脑的变化：80.4%的ET脑有小脑退行性改变，表现为数量增加 鱼雷和浦肯野细胞(PC)数量轻微减少(小脑等)，而19.6%的人有脑干路易体。 因此，在这一点上，我们已经描述了ET大脑的几个基本变化。两者的临床差异 病理上确定的ET亚型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是促进我们对小脑ET患者死后变化的了解(目标1A)和 Luy Body ET(Aim 1B)通过对PC神经元形态的详细研究。因为我们的分析到目前为止 被限制在一个小脑半球的单个区域，我们将扩大我们的范围，将其他区域包括在内 小脑的功能解剖区域(目标1C)。通过目标1，我们将检验一个假设(疾病模型) ET各病理亚型。特定的目标2是建立临床特征和尸检之间的基本联系 脑部改变(临床-病理相关性)。在我们2002年的应用中，通过设计，临床评估是简短的和 间接(电话和录像带)。现在我们的目标是对175人进行全面的面对面临床评估 老年ET病例，我们预计其中42人将在这个五年计划期间死亡。通过这样做，我们可以开始识别 两种病理亚型ET患者的特殊临床特征。我们的目标是 通过(1)增加我们对ET的病理解剖的了解和(2)锻造所需的 医生在活着的病人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存在联系。

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 46 ET brains and 32 control brains, we have discovered that, indeed, there are identifiable pathological changes in the ET brain: 80.4% 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 19.6% 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. Because our analyses have thus far been 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). Through Aim 1, we will test a hypothesis (disease model) for each pathological subtype of ET. 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, 42 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.