Clinical Pathological Study of Cognitive Impairment in Essential Tremor

项目总结 原发性震颤(ET)是最常见的神经系统疾病之一。虽然最多的 ET可识别的临床特征是震颤，有新的证据表明非运动特征 (特别是认知功能障碍)可能存在。越来越多的研究表明，ET 与年龄匹配的对照组相比，患者的认知表现较差，但认知特征 在有认知问题的ET患者中，还没有完全的特征。在某些ET中 患者的认知问题相当严重。最近的流行病学研究表明 证明ET患者更有可能患有轻度认知障碍(MCI) 年龄匹配的对照组，痴呆症的风险增加(相对风险=1.64-1.89)。而ET 似乎是认知障碍发展的危险因素，认知障碍的原因 ET的损害目前尚不清楚。有早期证据表明，ET可能与 并增加了发生以tau病理为特征的疾病的风险。总目标 建议的研究是确定认知障碍的临床和病理特征 与ET相关的损害。为了实现这一目标，我们计划进行神经心理学 受试者的生前检查和病后神经病理学检查 Essential Tremor中央脑库(ETCBR)，一个具有良好特征的250个样本 已同意脑捐献的老年ET病例(R01NS042859，E.Louis)。 虽然他们的震颤有很好的特征，但神经心理测试仅限于 总体全球认知评估。这项拟议研究的一个中心假设是 大多数患有MCI和痴呆症的ET患者会有以tau为特征的障碍 病理学(阿尔茨海默病或进行性核上性麻痹)。我们五年的研究 提案有两个具体目标：目标1：描述认知特征并指定诊断 在基线和每18个月对250名ET患者的正常认知、MCI或痴呆进行评估。目标 2：分析100例ET患者的神经病理特征 1-5岁，包括患有认知障碍的70岁。这一目标将包括神经病理学和 生物化学研究，以确定tau蛋白的分子特征。这项研究将测试 几种假想的临床和临床-病理关系(假说1A-C、2A-C)。 我们期望这项拟议的研究将阐明ET和 适当的时候，塑造有认知症状的ET患者的咨询和治疗。我们 预计这些数据将成为研究和表征的黄金标准数据 未来几年内ET的认知障碍，以及未来研究人员的组织资源。

PROJECT SUMMARY Essential tremor (ET) is one of the most prevalent neurological diseases. Although the most recognizable clinical feature of ET is tremor, there is emerging evidence that non-motor features (esp. cognitive dysfunction) may be present. A growing number of studies are showing that ET patients have poorer cognitive performance than age-matched controls, yet the cognitive profile among ET patients with cognitive problems has yet to be fully characterized. In some ET patients, the cognitive problems are quite severe. Recent epidemiological studies have demonstrated that ET patients are more likely to have mild cognitive impairment (MCI) than age-matched controls, and an increased risk of dementia (relative risk = 1.64 - 1.89). While ET appears to be a risk factor for the development of cognitive impairment, the cause of cognitive impairment in ET is not currently known. There is early evidence that ET may be associated with an increased risk of developing disorders characterized by tau pathology. The overall goal of the proposed research is to determine the clinical and pathological characteristics of cognitive impairment associated with ET. To accomplish this goal, we plan to perform neuropsychological examinations during life and post-morbid neuropathological examinations on participants in the Essential Tremor Centralized Brain Repository (ETCBR), a well-characterized sample of 250 elderly ET cases who have all already agreed to brain donation (R01NS042859, E. Louis). While their tremor has been well-characterized, neuropsychological testing has been limited to a gross global cognitive evaluation. A central hypothesis for the proposed research is that the majority of ET patients with MCI and dementia will have disorders characterized by tau pathology (Alzheimer's disease or progressive supranuclear palsy). Our 5-year research proposal has two specific aims: Aim 1: Characterize the cognitive profile and assign diagnoses of normal cognition, MCI, or dementia in 250 ET patients at baseline and every 18 months. Aim 2: Characterize the neuropathological features of 100 brains of patients with ET harvested in Years 1 - 5, including >70 with cognitive impairment. This aim will include neuropathological and biochemical studies to characterize the molecular signature of the tau protein. The study will test several hypothesized clinical and clinical-pathological relationships (Hypotheses 1A-C, 2A-C). We expect that the proposed research will elucidate the processes of dementia in ET and, in due course, shape the counseling and treatment of ET patients with cognitive symptoms. We anticipate that these will be the gold standard data for the study and characterization of cognitive impairment in ET for years to come, and a tissue resource for future investigators.