The University of Kentucky MarkVCID Biomarker Validation Cohort: Development of a Toolbox to Advance VCID Interventional Studies

摘要 MarkVCID联盟的成立是为了发现和跨站点验证脑部小血管疾病(CSVD)的生物标记物，最终目标是开发一个生物标记物工具箱，该工具箱将具有诊断、疾病分层和纵向跟踪实用功能，用于未来的血管对认知损害和痴呆(VCID)的临床试验。肯塔基大学(英国)在2016年的初始资助期被选为MarkVCID的七个地点之一。作为中风带的中心，肯塔基州是心脑血管疾病高发的州，肯塔基大学是中风和痴呆症的卓越中心，英国是指定的综合中风中心，并拥有NIA阿尔茨海默病研究中心(ADRC)。在我们目前的资助期间，我们成功招募了126人(超过我们最初建议的120人)，这些人具有不同程度的心血管风险因素，其中很大一部分人定义为主观记忆主诉(SMC)，其中一些被定义为轻度认知障碍(MCI)。所有参与者都接受了MarkVCID磁共振成套检查、采血、神经心理学和临床评估，而四分之一的人还贡献了脑脊液。重要的是，所有参与者都同意进行尸检；这是我们在MarkVCID招聘之初就提出的要求。英国MarkVCID全面参与了除OCT-A试剂盒之外的每一种生物标志物试剂盒的验证。我们还领导了两个生物标志物试剂盒：白质生长和回归试剂盒和脑脊液PlGF试剂盒。在根据RFA-NS-16-020与UH3NS100606相关的这次更新中，我们建议将我们的队列扩大到200人，特别侧重于扩大对具有SMCS和MCI的不同人群和个人的招聘。在参与了所有MRI和液体生物标记物试剂盒的协调、仪器验证以及现在的生物验证之后，我们准备为该联盟的继续做出重大贡献。我们提出了三个具体目标来实现RFA-NS-21-005中列出的目标：具体目标1：保留和扩大丰富的多样化队列，以满足患有主观记忆主诉和认知障碍的高风险脑部小血管疾病的个人。具体目标2：与该联盟合作，促进数据、成像和流体共享，并加快我们对我们队列中MarkVCID候选生物标记物的验证。具体目标3：充分参与联盟内的领导角色，并为寻求探索生物标记物和/或开发治疗VCID的新的临床试验和干预研究的内部和外部研究人员提供咨询能力。

ABSTRACT The MarkVCID consortium was established to discover and cross-site validate biomarkers of cerebral small vessel disease (cSVD) with an ultimate goal of developing a toolbox of biomarkers that will have diagnostic, disease stratification, and longitudinal tracking utility for future vascular contributions to cognitive impairment and dementia (VCID) clinical trials. The University of Kentucky (UK) was selected as one of the seven MarkVCID sites in its initial funding period in 2016. Being in the heart of the stroke belt, Kentucky is a state with a high prevalence of cardiovascular and cerebrovascular disease, and the University of Kentucky is a Center of Excellence for Stroke and Dementia, with UK being a designated Comprehensive Stroke Center and has an NIA Alzheimer's Disease Research Center (ADRC). During our current funding period, we successfully recruited a cohort of 126 individuals (exceeding our originally proposed 120) with varying levels of cardiovascular risk factors and a large proportion of whom have defined subjective memory complaints (SMCs), with some defined as mild cognitive impairment (MCI). All participants underwent the MarkVCID MRI battery, blood collection, and neuropsychological and clinical assessment, while one quarter also contributed CSF. Importantly, all participants have consented to autopsy; a requirement we initiated at the beginning of our MarkVCID recruitment. UK MarkVCID has fully participated in the validation of every biomarker kit except the OCT-A kit. We have also led two biomarker kits: the White Matter Growth and Regression kit and the CSF PlGF kit. In this renewal connected to UH3NS100606 under RFA-NS-16-020, we propose to expand our cohort to 200 individuals, with a particular focus on expanding recruitment of diverse populations and individuals with SMCs and MCI. Having participated in the harmonization, instrumental validation, and now biological validation, of all MRI and fluid biomarker kits, we are poised to make significant contributions in the continuation of the consortium. We have proposed three Specific Aims to achieve the goals laid out in RFA- NS-21-005: Specific Aim 1: Retain and expand a diverse cohort enriched for individuals with subjective memory complaints and cognitive impairment at high risk for cerebral small vessel disease. Specific Aim 2: Work with the consortium to facilitate data, imaging, and fluid sharing and accelerate our validation of the MarkVCID candidate biomarkers in our cohort. Specific Aim 3: Fully engage in leadership roles within the consortium and serve in a consulting capacity for both internal and external researchers seeking to explore biomarkers and or develop new clinical trials and interventional studies for the treatment of VCID.