Tracking longitudinal change in presymptomatic genetic prion disease (TLC-Pre-gPrD)

追踪症状前遗传性朊病毒病的纵向变化（TLC-Pre-gPrD）

• 批准号: 10455529
• 负责人: MICHAEL D GESCHWIND
• 金额: $ 114.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455529
• 关键词: Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Behavioral; Biological; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Brain Diseases; Cell Nucleus; Clinical; Clinical Research; Clinical Trials; Cognitive; Collection; Creutzfeldt-Jakob Syndrome; Data; Development; Diffuse; Disease; Disease Progression; Early Diagnosis; Family; Future; Gender; Gene Mutation; Genetic; Genetic Diseases; Genetic Risk; Goals; Human; Huntington Disease; Image; Inherited; Inner Nuclear Layer; Knowledge; Light; Liquid substance; Literature; Magnetic Resonance Imaging; Measures; Methods; Motor; Mutation; Neurodegenerative Disorders; Neurologic; Neuropsychological Tests; Olfactory Mucosa; Onset of illness; Optical Coherence Tomography; Outcome Measure; Patients; Persons; Phase; Plasma; Plasma Proteins; PrP gene; Prion Diseases; Rare Diseases; Retina; Serum; Skin; Swab; Symptoms; Testing; Therapeutic Trials; Thick; Time; Visit; brain magnetic resonance imaging; brain volume; cohort; daily functioning; design; detection method; genetic predictors; genetic testing; mutation carrier; neurofilament; phase 1 study; potential biomarker; pre-clinical; prevent; processing speed; programs; rate of change; recruit; targeted treatment; tau Proteins; treatment trial

Project Summary/Abstract The main goal of this project is to identify and develop biomarkers for treatment trials in presymptomatic genetic prion disease (PreSx gPrD). Most PrDs are potentially transmissible and rapidly progressive; all are fatal. As has been shown in a related disorder, Alzheimer’s disease, it is critical to develop early detection methods and biomarkers so that potential treatments can be given in early pre-presymptomatic (pre-clinical) phases when they have the best chance of working. Approximately 15% of human prion diseases (PrDs) are genetic, caused by mutations in the prion protein gene, PRNP. Because a simple genetic blood test can identify PRNP mutation carriers from families with gPrD, we can identify those with mutations prior to their developing symptoms (presymptomatic; PreSx); this group is an ideal target for therapeutic trials, to delay or even prevent, clinical onset. Similar methods are being used in autosomal dominant forms of genetic Alzheimer’s disease, such as with the Alzheimer’s Disease Prevention Initiative (API) and the Dominantly Inherited Alzheimer’s Disease Network (DIAN) studies. Therapies for PrD are currently under development, but to prepare for these trials it is necessary to identify markers sensitive to biological changes in pre-clinical stages, when symptoms have not yet developed. Our preliminary data suggest that such biological changes (biomarkers) can be measured in PreSx gPrDs and include brain volume, MRI mean diffusivity, cognitive & quantified motor assessments, retinal layer thickness and possibly CSF and plasma proteins. Over five years, we will recruit ~80 PreSx gPrD mutation carriers and ~40 age & gender-matched controls without PRNP mutations (non-carriers) from gPrD families. Subjects will have serial annual visits, for at least three years, that include: neurological exam, neuropsychological testing, functional scores, blood and CSF collection, olfactory mucosal swabbings, skin biopsies, brain MRI, and optical coherence tomography. We will establish rates of change of various biomarkers in PreSx mutation carriers vs. controls, to determine the best outcome measures for PreSx gPrD treatment trials. Our aims are: Aim 1. Characterize the rates of biomarker change in PreSx Slow-gPrD. We hypothesize that, compared with controls, PreSx Slow-gPrD will show greater rates of: A) cortical MD elevation, B) decline on quantitative motor testing, & C) decline in processing speed. Aim 2. Characterize the rates of biomarker change in PreSx Fast-gPrD. We hypothesize that, compared with controls, PreSx Fast-gPrD will show great rates of: A) deep nuclei (putaminal) MD reduction, B) Greater rates of decline on quantified motor testing, & C) decline in processing speed Exploratory Aims. A) We hypothesize that subjects with positive RT-QuIC assays will have more rapid imaging and clinical changes than RT-QuIC negative subjects. B) Fast and Slow PreSx gPrD will have greater rates of 1. elevation of certain CSF & serum biomarkers, 2. cognitive & motor decline, and 3. cortical volume loss, whereas only PreSx Slow gPrD will have a greater rate of decline in INL thickness, than controls.

项目总结/摘要 这个项目的主要目标是识别和开发用于症状前治疗试验的生物标志物 遗传性朊病毒病（PreSx gPrD）。大多数PrD具有潜在的传播性和快速进展性;所有PrD都是 致命的正如在一个相关的疾病，阿尔茨海默氏病，这是至关重要的发展早期发现 方法和生物标志物，以便在早期症状前（临床前）给予潜在治疗 当他们有最好的工作机会。大约15%的人类朊病毒疾病（PrD）是 遗传性的，由朊病毒蛋白基因（PRNP）突变引起。因为一个简单的基因血液测试可以 从具有gPrD的家族中鉴定PRNP突变携带者，我们可以鉴定那些在其突变之前具有突变的人。 出现症状（前驱症状; PreSx）;这一组是治疗试验的理想目标，以延迟或 甚至预防临床发病类似的方法也被用于常染色体显性遗传形式的遗传学研究。 阿尔茨海默氏病，如阿尔茨海默氏病预防倡议（API）和显性阿尔茨海默氏病， 遗传性阿尔茨海默病网络（DIAN）研究。PrD的治疗方法目前正在开发中，但 为了准备这些试验，有必要鉴定对临床前的生物学变化敏感的标记物， 阶段，症状尚未出现。我们的初步数据表明，这种生物学变化 （生物标志物）可以在PreSx gPrD中测量，并且包括脑体积、MRI平均扩散率、认知& 定量运动评估、视网膜层厚度以及可能的CSF和血浆蛋白。 在五年内，我们将招募约80名PreSx gPrD突变携带者和约40名年龄和性别匹配的 没有来自gPrD家族的PRNP突变的对照（非携带者）。受试者将接受连续年度访视， 至少三年，包括：神经系统检查，神经心理测试，功能评分，血液和 CSF采集、嗅粘膜拭子、皮肤活检、脑MRI和光学相干断层扫描。我们 将建立PreSx突变携带者与对照组中各种生物标志物的变化率，以确定 PreSx gPrD治疗试验的最佳结局指标。我们的目标是：目标1。描述以下比率的特征： PreSx Slow-gPrD的生物标志物变化。我们假设，与对照组相比，PreSx Slow-gPrD 显示出更大的比率：A）皮质MD升高，B）定量运动测试下降，& C） 处理速度。目标2.表征PreSx Fast-gPrD中生物标志物的变化率。我们假设 与对照组相比，PreSx Fast-gPrD将显示更高的：A）深核（壳核）MD 减少，B）量化运动测试的下降率更大，& C）处理速度下降 探索目标。A）我们假设具有阳性RT-QuIC测定的受试者将具有更快速的 与RT-QuIC阴性受试者相比，影像学和临床变化。B）快速和慢速PreSx gPrD将具有更大的 率1。某些CSF和血清生物标志物的升高，2.认知和运动能力下降，以及3.皮质体积 与对照相比，只有PreSx Slow gPrD具有更大的INL厚度下降速率。