Rapidly Progressive Dementia: Moving Beyond CJD

快速进展性痴呆：超越克雅氏病

• 批准号: 10085838
• 负责人: GREGORY SCOTT DAY
• 金额: $ 15.68万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085838
• 关键词: Active Learning; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-42; Autoimmune Process; Autoimmune encephalitis; Autopsy; Biological; Biological Markers; Cell Count; Cerebrospinal Fluid; Chitinase; Classification; Clinical; Clinical Research; Cognition; Consensus; Counseling; Creutzfeldt-Jakob Syndrome; Dementia; Detection; Development; Diagnosis; Diagnostic; Disease; Early identification; Enrollment; Ensure; Etiology; Evaluation; Functional disorder; Future; Gender; Goals; Image; Individual; Interview; Investigation; Knowledge; Lead; Legal patent; Lewy Bodies; Light; Longitudinal Studies; Measures; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Neurodegenerative Disorders; Neurologic Examination; Neurologist; Neuronal Injury; Neuropsychological Tests; Observational Study; Oligoclonal Bands; Outcome; Participant; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Performance; Phenotype; Positioning Attribute; Proteins; Rare Diseases; Research; Research Personnel; Resources; Serum; Severities; Signs and Symptoms; Societies; Source; Specialist; Standardization; Symptoms; Synapses; Testing; Therapeutic Trials; Universities; Vascular Dementia; Visit; Washington; accurate diagnosis; cohort; experience; functional disability; improved; improved outcome; in vivo; inflammatory marker; medical schools; mixed dementia; neurocognitive test; neurofilament; neurogranin; neuroimaging; neuroinflammation; neuron loss; neuropathology; novel therapeutics; patient oriented; patient oriented research; progression marker; prospective; rapid diagnosis; research clinical testing; skills; synaptosomal-associated protein 25

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.

项目概要/摘要 快速进展性痴呆 (RPD) 患者占痴呆病例的 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)。更多的 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明显可治疗的患者 RPD 的自身免疫原因。然而，临床特征和结果存在显着重叠 研究常常混淆 RPD 的病因诊断，导致诊断延迟、漏诊 治疗的机会和较差的结果。迫切需要确定临床特征和 定义患有 RPD 特定原因的患者的生物特征，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导致症状下降。该项目将解决这些 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] 和神经影像学）以及定义患者的生物流体生物标志物特征 AD、ADRD 和 AE 导致的 RPD。共识病因诊断将根据独立的结果建立 由多名神经科医生审查可用的临床信息（目标 1）。 AD 神经病理学的生物标志物， 将在就诊时获得的脑脊液中测量神经元损伤、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 个体 参加了华盛顿大学医学院 (WUSM) 的记忆和衰老的平行研究。这 这项研究的结果将定义区分 RPD 患者的临床特征和 CSF 生物标志物 由于 AD、ADRD 和 AE（目标 2A），促进早期识别明显可治疗的患者 RPD 的自身免疫原因（目标 2B）。通过定义临床和脑脊液生物标志物谱来区分 患有快速且典型进展性 AD 和 ADRD 的个体，研究结果还将告知以下人员的贡献 AD神经病理学、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）。尽管该项目将重点关注 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，帮助识别机制 影响症状减轻的速度和患者的治疗结果。这些机制可以通过 未来的治疗试验，目标是改善快速且通常进行性进展的患者的结果 失智。戴博士将通过说教和体验获得以患者为导向的研究的必要技能 在 WUSM 和附属奈特阿尔茨海默病研究中心完成的学习，并将受益 来自以患者为中心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，包括博士。约翰·C·莫里斯、安妮·M·费根、博·M·安塞斯和迈克尔·D·杰施温德。