Rapidly Progressive Dementia: Moving Beyond CJD

项目摘要/摘要 快速进展性痴呆(RPD)患者占痴呆患者的3%-4%，其中大多数 归因于克雅氏病(CJD)、阿尔茨海默病(AD)或AD相关痴呆(ADRD)。更多 最近，对自身免疫性脑炎(AE)作为RPD病因的认识促进了RPD的发展 诊断方法，强调需要迅速检测出显著可治疗的患者 RPD的自身免疫性病因。然而，在呈现的临床特征和结果上有显著的重叠 检查常常混淆RPD的病因诊断，导致诊断延误、漏诊 治疗机会和较差的结果。迫切需要确定其临床特征和 确定具有特定原因的RPD患者的生物学特征，并开发可量化的生物标记物 反映疾病病理，预测进展，并告知神经元丢失的贡献， 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、调查结果(包括血清和 脑脊液检查[脑脊液]和神经成像)，以及定义患者的生物流体生物标记物特征 AD、ADRD和AE所致的RPD。一致的病因诊断将建立在独立的 多位神经科医生对现有临床信息的回顾(目标1)。AD神经病理的生物标记物， 神经损伤、神经炎症和突触功能障碍将在就诊时从脑脊液中检测出来。 来自RPD患者，以及来自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)参加了关于记忆和衰老的平行研究。这个 这项研究的结果将明确临床特征和脑脊液生物标记物，以区分RPD患者 由于AD、ADRD和AE(AIM 2A)，有助于早期识别可显著治疗的患者 RPD的自身免疫原因(目标2B)。通过定义临床和脑脊液生物标记物特征来区分 患有快速和典型进展性AD和ADRD的人，研究结果也将有助于 AD的神经病理、神经元损伤、神经炎症和突触功能障碍对表型表达的影响 AD和ADRD(目标3)。虽然这个项目的重点是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，帮助确定发病机制 这会影响症状下降率和患者预后。这些机制可以通过 未来的治疗试验，目标是改善快速和典型进展性糖尿病患者的结果 痴呆症。戴博士将通过授课和经验获得以患者为导向的研究方面的必要技能 在WUSM和附属的骑士阿尔茨海默病研究中心完成了学习，并将受益 来自以患者为导向的痴呆症研究和生物流体领域知名专家/导师的支持 生物标志物测量，包括约翰·C·莫里斯博士、安妮·M·费根博士、博·曼斯博士和迈克尔·D·格施温德博士。

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.