Rapidly Progressive Dementia: Moving Beyond CJD

项目概要/摘要 患有快速进展性痴呆（RPD）的患者占痴呆病例的3-4%，其中大多数 在一些实施方案中，所述疾病可归因于克雅氏病（CJD）、阿尔茨海默病（AD）或AD相关性痴呆（ADRD）。更 最近，认识到自身免疫性脑炎（AE）是RPD的一个原因， 诊断方法，强调需要迅速检测患者的显着治疗 RPD的自身免疫原因。然而，在目前的临床特征和结果的显着重叠， 调查往往混淆RPD的病因诊断，导致诊断延误，错过 治疗机会和较差的结果。迫切需要确定临床特征， 生物学特征，定义具有RPD特定原因的患者，并开发可量化的生物标志物 反映疾病病理学，预测进展并告知神经元损失的贡献， 神经炎症和突触功能障碍与症状性下降率的关系。该项目将解决这些问题 通过系统地定义临床特征、研究结果（包括血清和 脑脊液测试[CSF]和神经成像），以及定义患者 AD、ADRD和AE导致的RPD。将在独立的 多位神经科医生对可用临床信息进行审查（目标1）。AD神经病理学的生物标志物， 将在就诊时获得的CSF中测量神经元损伤、神经炎症和突触功能障碍 来自RPD患者以及年龄和性别相似的典型进行性AD和ADRD患者 在华盛顿大学医学院（WUSM）参加了记忆和衰老的平行研究。的 本研究的结果将确定区分RPD患者的临床特征和CSF生物标志物 由于AD、ADRD和AE（目的2A），有助于早期识别具有显著可治疗性的患者 RPD的自身免疫原因（目的2B）。通过定义临床和CSF生物标志物特征， 患有快速和典型进行性AD和ADRD的个体，研究结果还将为以下方面的贡献提供信息： AD的神经病理、神经元损伤、神经炎症和突触功能障碍以表型表达为主 AD和ADRD（目标3）。虽然本项目将重点关注RPD患者，但研究结果和经验 将为所有痴呆症患者的评估和诊断提供信息， 影响症状下降率和患者预后的因素。这些机制可以通过以下方式来实现： 未来的治疗试验，目标是改善快速和典型进展性 痴呆戴博士将获得必要的技能，在以病人为导向的研究，通过教学和经验 学习完成WUSM和附属骑士阿尔茨海默病研究中心，并将受益 在以患者为导向的痴呆症研究和生物流体方面， 生物标志物测量，包括John C Morris，Anne M Fagan，Beau M Ances和Michael D Geschwind博士

Project Summary / Abstract Patients with rapidly progressive dementia (RPD) account for 3-4% of dementia cases, with the majority attributed to Creutzfeldt-Jakob disease (CJD), Alzheimer disease (AD) or AD-related dementias (ADRD). More recently, recognition of autoimmune encephalitis (AE) as a cause of RPD has catalyzed the development of diagnostic approaches that emphasize the need for expeditious detection of patients with eminently treatable autoimmune causes of RPD. However, remarkable overlap in the presenting clinical features and results of investigations often confounds the etiologic diagnoses of RPD, contributing to diagnostic delays, missed opportunities for treatment and poorer outcomes. There is a critical need to determine the clinical features and biological signatures that define patients with specific causes of RPD, and to develop quantifiable biomarkers that reflect disease pathology, predict progression and inform the contributions of neuronal loss, neuroinflammation and synaptic dysfunction to rates of symptomatic decline. This project will address these needs by systematically defining the clinical features, results of investigations (including serum and cerebrospinal fluid tests [CSF], and neuroimaging), and biofluid biomarker signatures that define patients with RPD due to AD, ADRD and AE. Consensus etiologic diagnoses will be established following independent review of available clinical information by multiple neurologists (Aim 1). Biomarkers of AD neuropathology, neuronal injury, neuroinflammation and synaptic dysfunction will be measured in CSF obtained at presentation from RPD patients, and from age- and gender-similar individuals with typically progressive AD and ADRD enrolled in parallel studies of memory and aging at Washington University School of Medicine (WUSM). The results of this study will define the clinical features and CSF biomarkers that differentiate patients with RPD due to AD, ADRD and AE (Aim 2A), facilitating early identification of patients with eminently treatable autoimmune causes of RPD (Aim 2B). By defining the clinical and CSF biomarker profiles that distinguish individuals with rapid and typically progressive AD and ADRD, study results will also inform the contributions of AD neuropathology, neuronal injury, neuroinflammation and synaptic dysfunction to the phenotypic expression of AD and ADRD (Aim 3). Although this project will focus on patients with RPD, study findings and experience will inform the assessment and diagnosis of all dementia patients, aiding in the identification of mechanisms that affect rates of symptomatic decline and patient outcomes. These mechanisms may be targeted through future therapeutic trials, with the goal of improving outcomes in patients with rapid and typically progressive dementia. Dr. Day will acquire necessary skills in patient-oriented research through didactic and experiential learning completed at WUSM and the affiliated Knight Alzheimer Disease Research Center, and will benefit from the support of well established experts/mentors in patient-oriented dementia research and biofluid biomarker measures, including Drs. John C Morris, Anne M Fagan, Beau M Ances and Michael D Geschwind.