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: 10621258
• 负责人: MICHAEL D GESCHWIND
• 金额: $ 108.62万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621258
• 关键词: Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease related dementia; 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; 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; autosome; biomarker identification; 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.

项目概要/摘要 该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) 具有潜在传染性且进展迅速； 正如相关疾病阿尔茨海默病所表明的那样，早期检测至关重要。 方法和生物标志物，以便可以在症状前早期（临床前）给予潜在的治疗 大约 15% 的人类朊病毒病 (PrD) 处于最有可能发挥作用的阶段。 遗传，由朊病毒蛋白基因突变引起，PRNP 因为简单的遗传血液测试就可以。 从患有 gPrD 的家庭中识别 PRNP 突变携带者，我们可以在他们之前识别出那些携带突变的人 出现症状（症状前；PreSx）；该群体是治疗试验的理想目标，以延迟或 类似的方法也被用于常染色体显性遗传形式的临床发病。 阿尔茨海默病，例如阿尔茨海默病预防计划 (API) 和 Dominantly 遗传性阿尔茨海默氏病网络 (DIAN) 研究目前正在开发中，但是。 为了准备这些试验，有必要在临床前确定对生物变化敏感的标记物 阶段，当症状尚未出现时，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，包括脑容量、MRI 平均扩散率、认知和 量化运动评估、视网膜层厚度以及可能的脑脊液和血浆蛋白。 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 来自 gPrD 家族的没有 PRNP 突变的对照（非携带者）将每年进行连续访视。 至少三年，包括：神经系统检查、神经心理学测试、功能评分、血液和 脑脊液采集、嗅粘膜拭子、皮肤活检、脑部 MRI 和光学相干断层扫描。 将确定 PreSx 突变携带者与对照者中各种生物标志物的变化率，以确定 PreSx gPrD 治疗试验的最佳结果衡量标准是： 目标 1. 描述发生率。 我们发现，与对照组相比，PreSx Slow-gPrD 中的生物标志物发生变化。 显示更大的比率：A) 皮质 MD 升高，B) 定量运动测试下降，&C) 下降 目标 2. 表征 PreSx Fast-gPrD 中生物标志物变化的速率。 与对照相比，PreSx Fast-gPrD 将显示出很高的比率：A) 深部核（壳核）MD 减少，B) 量化电机测试的下降率更大，&C) 处理速度下降 探索性目标 A) 我们勇敢地说，RT-QuIC 检测结果呈阳性的受试者将具有更快的速度。 与 RT-QuIC 阴性受试者相比，B) 快速和慢速 PreSx gPrD 的影像学和临床变化会更大。 1. 某些脑脊液和血清生物标志物升高，2. 认知和运动能力下降，以及 3. 皮质体积的发生率 损失，而只有 PreSx Slow gPrD 的 INL 厚度下降率比对照更大。

项目成果

Retinal arteriolar parameters as a surrogate marker of intracranial vascular pathology.

视网膜小动脉参数作为颅内血管病理学的替代标志。

• 发表时间: 2022
• 作者: Abdelhak, Ahmed;Solomon, Isaac;Montes, Shivany Condor;Saias, Alexandra;Cordano, Christian;Asken, Breton;Fonseca, Corrina;Oertel, Frederike Cosima;Arfanakis, Konstantinos;Staffaroni, Adam M;Kramer, Joel H;Geschwind, Michael;Miller, Bruce L;Ela
• 通讯作者: Ela