Validation of small vessel vascular contributions to cognitive impairment and dementia (VCID) biomarkers

项目摘要/摘要： 小血管相关血管对认知损害和痴呆的贡献(VCID)是老年人认知功能障碍的第二大原因。然而，与VCID相关的关键血管过程的定量生物标记物仍然缺乏，这些标记物适合作为临床试验的终点。本申请的目标是1)通过对具有认知主诉和/或可能与小血管疾病相关的认知损害和痴呆的早期症状体征的不同ALL患者进行纵向研究，参与NINDS选择的最多6个生物标记物的多站点临床验证；2)如果CVR生物标记物被选择进入下一阶段研究，则领导对所有患者的脑血管反应性(CVR)生物标记物的多站点临床验证。本申请是根据RFA-NS-16-020对UH2/3 NS100588的续展。作为上述RFA的资助参与站点之一，以下简称MarkVCID I研究，我们在JHU的团队为联合体做出了重大贡献：1)在UH2阶段，我们开发了CVR MRI候选生物标记物，并收集数据支持其被NINDS选择成为过渡到UH3阶段的11个生物标记物之一；2)在UH2阶段，我们与其他站点合作标准化MRI、生物流体、临床和神经心理测量，并实施了本站点本地其他站点提出的候选生物标记物；3)在UH3阶段，我们参与了NINDS批准的生物标记物的多点仪器和生物验证；4)在UH3阶段，我们领导了CVR候选生物标记物的多点仪器和生物验证。重要的是，我们的网站拥有执行目前正在考虑的11个生物标记物中的任何一个所需的科学专业知识和设备；5)我们参加了所有联盟范围内的活动，如年度会议、委员会会议和电话会议。在本申请中，我们提出了四个具体目标。在该项目的头两年，AIM 1将招募220名来自美国临床环境中典型的不同全来者的参与者，并收集NINDS批准的生物标记物测量。目标2将在该项目的后三年对至少200名参与者进行纵向跟踪。AIM 3将提供投入并参与联合会范围内的活动，如担任委员会成员、讨论议定书、出席年度会议并在会上发言、参与多地点数据处理和验证以及与联合会内外的研究人员分享数据和生物谱。在目标4中，如果脑血管反应性(CVR)生物标记物被选择进入下一阶段，我们将领导脑血管反应性(CVR)生物标志物的多点临床验证。影响：在这个项目完成后，我们将开发出一套VCID生物标记物，为VCID的未来临床试验做好准备，包括大型III期试验。

Project Summary/Abstract: Small-vessel-related vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of cognitive dysfunction in older individuals. However, quantitative biomarkers indexing key vascular processes related to VCID that are suitable for use as endpoints in clinical trials are still lacking. The goals of the present application are to 1) participate in the multi-site clinical validation of up to six biomarkers selected by the NINDS through a longitudinal study of diverse all-comers with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia potentially associated with small vessel disease; 2) lead the multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker in all-comers, if the CVR biomarker is selected to move onto the next-phase study. The present application is a Renewal of UH2/3 NS100588 under RFA-NS-16-020. As one of the funded participating sites of the above-mentioned RFA, hereafter referred to as MarkVCID I study, our team at JHU has made significant contributions to the Consortium: 1) In the UH2 phase, we developed a CVR MRI candidate biomarker and collected data to support its selection by the NINDS to become one of the eleven biomarkers that transited into the UH3 phase; 2) In the UH2 phase, we worked with other sites to standardize MRI, biofluid, clinical, and neuropsychological measures and implemented candidate biomarkers proposed by other sites locally at our site; 3) In the UH3 phase, we participated in the multi-site instrumental and biological validation of biomarkers approved by the NINDS; 4) In the UH3 phase, we led the multi-site instrumental and biological validation of the CVR candidate biomarker. Importantly, our site has the scientific expertise and equipment that are necessary to perform any of the 11 biomarkers currently under consideration; 5) We participated in all Consortium-wide activities such as annual conferences, committee meetings, and calls. In the present application, we propose four Specific Aims. Aim 1 will enroll 220 participants of diverse all-comers that are typical in clinical settings in the United States during the first two years of the project and collect the NINDS-approved biomarker measures. Aim 2 will conduct longitudinal follow-up in a minimum of 200 participants in the latter three years of the project. Aim 3 will provide inputs and participate in the Consortium-wide activities such as serving on committees, discussing protocols, attending and presenting in the annual conferences, participating in multi-site data processing and validation, and sharing data and biospecimens with researchers within and outside the Consortium. In Aim 4 we will lead multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker if CVR is selected to move on to the next phase. Impact: Upon the completion of this project, we will have developed a set of VCID biomarkers that are ready for future clinical trials, including large phase III trials, of VCID.