Clinical Pathological Study of Cognitive Impairment in Essential Tremor

描述（由申请人提供）：虽然特发性震颤（ET）最易识别的临床特征是震颤，但有新的证据表明存在非运动特征（特别是认知功能障碍）。越来越多的研究表明，ET患者的认知能力比年龄匹配的对照组差。在一些ET患者中，认知问题是严重的。此外，最近的流行病学研究表明，ET患者比年龄匹配的对照组更有可能患有轻度认知障碍（MCI），并且痴呆的风险增加。虽然ET似乎是认知障碍发展的风险因素，但目前尚不清楚原因。ET的小脑基础可能导致认知障碍，但还有其他证据表明ET与发展tau相关疾病（阿尔茨海默病[AD]和进行性核上性麻痹[PSP]）的风险增加有关。这种对机制理解的缺乏导致了困难的临床困境-目前没有办法基于他/她观察到的认知特征来推断给定的ET患者是否患有早期AD、早期PSP或仅仅是ET的预期认知特征。我们对患者没有预测性指南。下一步是什么？重要的是要最终确定ET的认知功能障碍的特点，并解开其组成原因。拟议研究的总体目标是完善我们对这种临床病理实体的理解。我们的目的是进行纵向神经心理学检查的350例ET和尸检神经病理学检查的110人死亡超过5年，匹配他们的220例尸检非ET的情况下。我们现在提出的新概念/新假设如下：i）由于尚不清楚的原因，ET本身易导致大脑中的tau蛋白病变;因此，推而广之，即使一个人要匹配认知障碍的水平，（正常认知、MCI或轻度痴呆），ET病例仍将比非ET病例具有更多的tau病理，ii）ET的tau蛋白病的性质/特征可能不同， iii）单独的ET病理可能是ET病例亚组中认知缺陷的主要原因，以及iv）在ET病例的混合中，应该可以将某些认知概况映射到某些病理上。我们的5年计划有两个目标：目的1：研究ET认知障碍的神经病理学基础。目标2：提供ET认知的第一个综合特征，并证明某些认知缺陷的严重程度可预测ET的非ET病理。我们期望这项研究将阐明ET痴呆的过程，并塑造有认知症状的ET患者的咨询和治疗。

DESCRIPTION (provided by applicant): Although the most recognizable clinical feature of essential tremor (ET) is tremor, there is emerging evidence that non-motor features (esp. cognitive dysfunction) are present. A growing number of studies show that ET patients have poorer cognitive performance than age-matched controls. In some ET patients, the cognitive problems are severe. Also, 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. While ET appears to be a risk factor for the development of cognitive impairment, the cause is not currently known. The cerebellar basis for ET could contribute to cognitive impairment, yet there is other evidence that ET is associated with an increased risk of developing tau-related disorders (Alzheimer's disease [AD] and progressive supranuclear palsy [PSP]). This absence of a mechanistic understanding results in a difficult clinical predicament - there is presently no way to deduce whether a given ET patient, based on his/her observed cognitive features, has early AD, early PSP, or merely the expected cognitive profile of ET. We have no predictive guidelines for patients. What are the next steps? It is important to conclusively characterize the cognitive impairment of ET and to disentangle its component causes. The overall goal of the proposed research is to refine our understanding of this clinical-pathological entity. We aim to perform longitudinal neuropsychological examinations on 350 ET cases and postmortem neuropathological examinations on 110 of these who die over 5 years, matching them to 220 autopsied non-ET cases. The novel concepts/new hypotheses we now put forward are as follows: i) for reasons that are as yet unclear, ET itself predisposes to tauopathic changes in the brain; thus, by extension, even if one were to match for level of cognitive impairment (normal cognition, MCI, or mild dementia), ET cases would still have more tau pathology than non-ET cases, ii) the nature/features of the tauopathy of ET is likely to differ from that of non-ET cases, iii) ET pathology alone, is likely to be the prime cause of cognitive deficits in a subgroup of ET cases, and iv) within the mix of ET cases, it should be possible to map certain cognitive profiles onto certain pathologies. Our 5-year proposal has two aims: AIM 1: To study the neuropathological basis of cognitive deficits in ET. AIM 2: To provide the first comprehensive characterization of cognition in ET and to demonstrate that the severity of certain cognitive deficits predicts non-ET pathology in ET. We expect that this research will elucidate the processes of dementia in ET and shape the counseling and treatment of ET patients with cognitive symptoms.