Pathogenesis of Essential Tremor: Cerebellar Metabolism

特发性震颤的发病机制：小脑代谢

• 批准号: 8109864
• 负责人: ELAN D LOUIS
• 金额: $ 65.06万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109864
• 关键词: Academic Medical Centers; Address; Affect; Age-Years; Anatomy; Animal Model; Antibodies; Area; Autopsy; Axon; Biology; Brain; Brain Stem; Brain region; Cell Count; Cerebellar vermis structure; Cerebellum; Clinical; Cytomegalovirus Infections; Data; Dendrites; Development; Disease; Disease model; Elderly; Equilibrium; Essential Tremor; Exhibits; Eye Movements; Functional disorder; Funding; Future; Genes; Goals; Grant; Hand; Health; Human; Intermediate Filament Proteins; Intermediate Filaments; Knowledge; Lateral; Lateral posterior nucleus of thalamus; Lesion; Letters; Lewy Bodies; Life; Link; Maintenance; Metabolism; Modeling; Morphology; Motor; Movement; Musculoskeletal Equilibrium; Nature; Neurofilament Proteins; Neurofilament-H; Neurofilament-L; Neurofilament-M; Neurons; Output; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathology; Patients; Persons; Pharmaceutical Preparations; Phosphorylation; Physicians; Physiological; Pontine structure; Positioning Attribute; Postmortem Changes; Proteins; Published Comment; Publishing; Purkinje Cells; Research; Research Personnel; Resources; Risk; Severities; Structure; Subthalamic structure; Swelling; Synapses; Telephone; Testing; Thalamic structure; Time; Tissues; Torpedo; Transgenic Mice; Videotape; Western Blotting; Work; alpha-internexin; base; case control; clinical Diagnosis; design; forging; mind control; motor control; nervous system disorder; neurofilament; neuronal cell body; novel; repository; research clinical testing; research study; response

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.

描述（由申请人提供）：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，这种疾病通常是渐进的。虽然它的发病率是帕金森病的20倍，但在我们最初的申请（2002年）时，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，几乎没有关于ET的潜在病理学的知识。虽然经常重申ET“没有病理学”，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特发性震颤集中脑库，以解决ET研究中的一个基本问题：能否根据特定脑区的形态学变化确定潜在的病理学？在集中收集并研究了51个ET脑和34个对照脑后，我们发现，ET脑中确实存在可识别的病理变化：82.3%的ET脑具有小脑退行性变化，表现为鱼雷数量增加和浦肯野细胞（PC）数量轻度减少（“小脑ET”），而17.7%具有脑干路易体。因此，在这一点上，我们已经描述了ET大脑中的几个基本变化。两种病理学鉴定的ET亚型之间的临床差异尚未得到充分研究。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神经元形态学的详细研究，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。在目标1A中，我们也将开始研究神经丝蛋白。由于我们以前的分析仅限于小脑半球的一个区域，我们将扩大范围，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。具体目标2是建立临床特征和死后脑变化之间的基本联系（临床-病理相关性）。在我们2002年的申请中，临床评价设计为简短和间接（电话和录像）。现在我们的目标是对175例老年ET病例进行全面的亲自临床评估，我们预计其中44例将在这五年的提案中死亡。这样做，我们可以开始确定特定的临床特征，表征患者与ET的两种病理亚型。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）在医生在活体患者中观察到的情况与我们在详细的尸检研究中发现的情况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尸检研究。在过去的5年中，我们对51个ET脑和34个对照脑进行了深入的收集和研究，发现ET脑确实存在可识别的病理变化。我们的目标是在这个竞争性的更新应用程序是推进我们的知识，死后的变化，在ET与浦肯野细胞（目的1）的更详细的定量形态学研究，并建立临床特征和死后的大脑变化（目的2）之间的基本联系。我们基于组织的研究将使我们处于独特的位置，开始解决有关ET的基本机制问题，并可能允许治疗医生预测患者一生中可能患有哪种ET亚型。