Clinical Pathological Study of Cognitive Impairment in Essential Tremor

特发性震颤（ET）是最常见的神经系统疾病之一。虽然它长期以来被认为是一个 纯粹的运动障碍，ET越来越被认为是更复杂的，随着对 认知功能障碍虽然认知缺陷可能是轻微的，但其他患者会痴呆。一些流行病学 研究表明，轻度认知障碍（MCI）的患病率较高， 阿尔茨海默病（AD）在ET。然而，ET中认知/痴呆的研究才刚刚起步。我们的数据有限， 不完整的-最基本的“什么”（即，临床特征，临床过程）和“为什么”（即，死后的基础）是 未知的总之，ET有认知的一面，我们对此知之甚少。在过去的4年里，我们有 建立并开始跟踪ET队列，以解决这些未知因素中的几个（临床病理学 认知功能障碍的研究（Study of Cognitive Impairment in ET，COGNET）。COGNET是规模最大的（230人注册; 195人活着）， 全面的、唯一的ET患者积极前瞻性队列。关键元素细节丰富，无电机， 纵向认知测试，共识认知诊断（正常认知[NC]，MCI，痴呆），以及 尸检数据这项研究要求进行一次基线评估和两次后续评估。目前，平均随访时间为 基线仅为1.50 ± 0.21年（范围= 0.31 - 2.29）。35人死亡。这些数据让我们开始 描述ET的认知功能障碍并研究其病理基础。然而，仍然存在大量的，明显的 知识的差距。首先，在临床上，ET的认知障碍是进行性的吗？他们的进步是否 比一般人的速度更快？MCI和痴呆的转化率是多少？有哪些 认知能力下降的临床预测因素AD的认知缺陷特征是否预示着更严重的临床症状 成果？事实证明，我们对认知障碍的预测因素、过程和结果几乎一无所知。 这些信息不能简单地从普通人群中获取。与一群 目前，COGNET已成功组装，并且正在进行纵向认知表型分析， 关于ET中认知缺陷的预测因子和动力学的重要预后问题（目的1）。第二、 在病理上，ET认知缺陷的基础是什么？我们的研究指出， 异质性基础，包括AD病理学。我们只有35个尸检样本，而我们对 认知缺陷的病理基础必须发展成熟（目标2）。我们现在建议继续 这一队列，增加了新的措施，以表征预测因子和结果的认知障碍的ET。 我们建议再招募100例ET病例（建议总数n = 295）。AIM 1.提供第一个长期 前瞻性，纵向表征ET的认知，以解决未回答的预后问题， ET中的认知损害（例如，向轻度认知障碍和痴呆症的转化率）。AIM 2.完成我们的临床病理- 通过比较100例ET与300例匹配的非ET病例的神经病理学特征，对ET进行逻辑研究， 识别特定神经病理学，特别是AD和其他tau蛋白病的认知预测因子。

Essential tremor (ET) is among the most prevalent neurological diseases. Although it was long considered a purely motor disorder, ET is increasingly being regarded as more complex, with an emerging recognition of cognitive dysfunction. While cognitive deficits can be mild, other patients dement. Several epidemiological studies reveal a higher prevalence of mild cognitive impairment (MCI) and 1.5 to 2-fold increased risk of Alzheimer's disease (AD) in ET. Yet the study of cognition/dementia in ET is nascent. Our data are limited and patchy - the most basic “whats” (i.e., clinical features, clinical course) and “whys” (i.e., postmortem basis) are uncharted. In sum, there is a cognitive side to ET, and we know little about it. For the past 4 years, we have established and begun to follow an ET cohort to address several of these unknowns (Clinical-Pathological Study of Cognitive Impairment in ET, COGNET). COGNET is the largest (230 enrolled; 195 living), most comprehensive, and only active prospective cohort of ET patients. Key elements are detailed, motor-free, longitudinal cognitive testing, consensus cognitive diagnoses (normal cognition [NC], MCI, dementia), and autopsy data. The study called for a baseline and two follow-up assessments. Currently, mean follow-up from baseline is only 1.50 ± 0.21 years (range = 0.31 - 2.29). Thirty-five died. The data have allowed us to begin to characterize the cognitive deficits in ET and study their pathological bases. Yet, there remain large, obvious gaps in knowledge. First, clinically, are the cognitive impairments in ET progressive? Do they progress at a faster rate than in the general population? What are the conversion rates to MCI and dementia? What are the clinical predictors of cognitive decline? Are cognitive deficits characteristic of AD predictive of worse clinical outcomes? It turns out that we know virtually nothing about the predictors, course and outcomes of cognitive impairments in ET, and such information cannot simply be taken from the general population. With a cohort now successfully assembled and longitudinal cognitive phenotyping ongoing, COGNET is poised to tackle important prognostic issues regarding the predictors and dynamics of cognitive deficits in ET (Aim 1). Second, pathologically, what is the basis for cognitive deficits in ET? Our studies point to heterogeneous deficits with heterogeneous bases, including AD pathologies. We only have 35 postmortems, and our nascent study of the pathological basis for cognitive deficits must grow and come to maturity (Aim 2). We now propose to continue this cohort, adding new measures to characterize the predictors and outcomes of cognitive impairments in ET. We propose enrolling 100 additional ET cases (proposed total n = 295). AIM 1. To provide the first long-term prospective, longitudinal characterization of cognition in ET to address unanswered prognostic questions about cognitive impairment in ET (e.g., conversion rates to MCI and dementia). AIM 2. To finalize our clinicopatho- logical study of ET by comparing the neuropathological features of 100 ET to 300 matched non-ET cases, and identifying the cognitive predictors of specific neuropathologies, particularly AD and other tauopathies.