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

摘要 MarkVCID联盟的成立旨在发现和跨中心验证脑小血管疾病（cSVD）的生物标志物，最终目标是开发一个生物标志物工具箱，该工具箱将具有诊断，疾病分层和纵向跟踪效用，用于未来血管对认知障碍和痴呆（VCID）临床试验的贡献。肯塔基州大学（英国）在2016年的初始资助期内被选为七个MarkVCID站点之一。作为中风带的心脏，肯塔基州是心脑血管疾病高发的州，肯塔基州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名具有不同程度心血管风险因素的个体（超过我们最初提出的120名），其中很大一部分人定义了主观记忆投诉（SMC），其中一些人定义为轻度认知障碍（MCI）。所有参与者都接受了MarkVCID MRI电池，血液收集，神经心理学和临床评估，而四分之一的参与者还贡献了CSF。重要的是，所有参与者都同意进行尸检;这是我们在MarkVCID招募之初就提出的要求。英国MarkVCID全面参与了除OCT-A试剂盒外的所有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：白色物质生长和消退试剂盒和CSF PlGF试剂盒。 在RFA-NS-16-020项下与UH 3 NS 100606相关的本次更新中，我们建议将队列扩大至200名个体，特别关注扩大不同人群以及SMC和MCI个体的招募。在参与了所有MRI和液体生物标志物试剂盒的协调、仪器验证以及现在的生物学验证之后，我们准备为该联盟的延续做出重大贡献。我们提出了三个具体目标，以实现RFA- NS-21-005中规定的目标：具体目标1：保留和扩展多样化队列，丰富脑小血管疾病高风险的主观记忆主诉和认知障碍个体。具体目标二：与联盟合作，促进数据，成像和液体共享，并加速我们对MarkVCID候选生物标志物的验证。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志物和/或开发新的临床试验和VCID治疗干预研究的内部和外部研究人员提供咨询服务。

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.