Rapidly Progressive Dementia: Moving Beyond CJD

快速进展性痴呆：超越克雅氏病

基本信息

批准号：
9805662
负责人：
GREGORY SCOTT DAY
金额：
$ 15.6万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9805662
关键词：
Active Learning Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker 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 off-patent patient oriented patient oriented research prospective rapid diagnosis research clinical testing skills synaptosomal-associated protein 25

项目摘要

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.

项目摘要 /摘要迅速进行性痴呆（RPD）的患者占痴呆症病例的3-4％，多数归因于Creutzfeldt-Jakob病（CJD），阿尔茨海默氏病（AD）或与AD相关的痴呆症（ADRD）。更多的最近，识别自身免疫性脑炎（AE）是RPD的原因诊断方法强调需要迅速检测出非常可治疗的患者 RPD的自身免疫性原因。但是，在提出的临床特征和结果中显着重叠调查通常会混淆RPD的病因诊断，导致诊断延迟，错过治疗的机会和较差的结果。确定临床特征和定义具有RPD特定原因的患者并开发可量化的生物标志物的生物学特征这反映了疾病病理，预测进展并告知神经元丧失的贡献，神经炎症和突触功能障碍，症状下降率。这个项目将解决这些问题通过系统地定义临床特征，调查结果（包括血清和血清和脑脊液测试[CSF]和神经影像学）以及定义患者患者的生物流体生物标志物特征 RPD由于AD，ADRD和AE。共识病因诊断将在独立之后建立多个神经科医生回顾可用的临床信息（AIM 1）。 AD神经病理学的生物标志物，神经元损伤，神经炎症和突触功能障碍将在CSF中测量在介绍时获得来自RPD患者，以及年龄和性别相似的人，通常是渐进式AD和ADRD 华盛顿大学医学院（WUSM）的记忆和衰老并行研究。这这项研究的结果将定义临床特征和CSF生物标志物，从而区分RPD患者由于AD，ADRD和AE（AIM 2A），促进了对患者的早期鉴定 RPD的自身免疫性原因（AIM 2B）。通过定义区分区分的临床和CSF生物标志物轮廓具有快速且通常是渐进的广告和ADRD的个人，研究结果还将为表型表达的AD神经病理学，神经元损伤，神经炎症和突触功能障碍 AD和ADRD（AIM 3）。尽管该项目将集中于RPD患者，但研究结果和经验将告知所有痴呆症患者的评估和诊断，有助于识别机制这会影响有症状的下降和患者预后的速度。这些机制可以通过未来的治疗试验，目的是改善快速且通常进行的患者的结局失智。 Day博士将通过教学和体验获得必要的技巧在WUSM和附属骑士阿尔茨海默氏病研究中心完成的学习，将受益在成熟的专家/导师的支持下，以患者为导向的痴呆研究和生物流体生物标志物措施，包括Drs。 John C Morris，Anne M Fagan，Beau M Ances和Michael D Geschwind。