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

项目摘要/摘要 这个项目的主要目标是识别和开发用于治疗症状前试验的生物标记物。 遗传性Pron病(PreSx GPRD)。大多数PRDS是潜在的可传播和快速发展的；所有的都是 致命的。正如一种相关的疾病--阿尔茨海默病所显示的那样，早期发现是至关重要的 方法和生物标志物，以便在症状前(临床前)早期给予潜在的治疗 当他们有最好的工作机会的时候。大约15%的人类朊病毒疾病(PRDS)是 基因，由PrNP基因突变引起。因为一个简单的基因血液测试就可以 从GPRD家系中鉴定PRNP突变携带者，我们可以在GPRD家系发生突变之前识别出突变携带者 出现症状(症状前；PreSx)；这一群体是治疗试验的理想目标，延迟或 甚至可以预防、临床发作。类似的方法也被用于常染色体显性遗传形式 阿尔茨海默氏症，如与阿尔茨海默氏症预防倡议(API)和多米尼克 遗传性阿尔茨海默病网络(DIAN)研究。珠江三角洲的治疗方法目前正在开发中，但 为了准备这些试验，有必要确定对临床前生物学变化敏感的标记物。 症状尚未发展的阶段。我们的初步数据表明，这种生物变化 (生物标记物)可以在PreSx gPrd中测量，包括脑体积、MRI平均弥散系数、认知和 量化运动评估，视网膜层厚度，可能还有脑脊液和血浆蛋白。 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人 GPRD家系中无PRNP突变的对照(非携带者)。受试者将有连续的年度访问， 至少三年，包括：神经学检查，神经心理测试，功能评分，血液和 脑脊液采集、嗅黏膜拭子、皮肤活检、脑核磁共振和光学相干断层扫描。我们 将建立PreSx突变携带者与对照中各种生物标记物的变化率，以确定 PreSx GPRD治疗试验的最佳结果衡量标准。我们的目标是：目标1.描述 PreSx慢GPRD的生物标志物改变。我们假设，与对照组相比，PreSx Slow-GPRD将 显示出更大的比率：A)皮质MD升高，B)定量运动测试下降，以及C)下降 处理速度。目的2.研究PreSx Fast-GPRD患者的生物标志物变化率。我们假设 与对照组相比，PreSx Fast-GPRD将显示出更高的比率：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 探索性目标。A)我们假设RT-QuIC检测呈阳性的受试者将有更快的 与RT-QuIC阴性的受试者相比，其影像和临床改变更明显。B)快速和缓慢的PreSx GPRD将拥有更大的 1.某些脑脊液和血清生物标志物升高的比率，2.认知和运动能力下降的比率，以及3.皮质体积 与对照组相比，只有PreSx慢速GPRD的INL厚度下降率更大。

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.