Small vessel disease biomarkers in a longitudinally-followed "stroke-belt" cohort

摘要 血管对认知障碍和痴呆的贡献（VCID）描述了认知障碍 由脑血管疾病或功能障碍引起的。VCID是阿尔茨海默病的常见并发症 疾病（AD），以及一个单一的痴呆症引起的实体。最常见的血管病变与 认知障碍是脑小血管病（SVD）。SVD很可能显著有助于 痴呆的临床表现，因此是疾病改善疗法的可行靶点， 无论是单独使用还是与AD靶向治疗联合使用。治疗发展的一个主要障碍 缺乏可预测SVD-VCID的存在和病程的生物标志物。在本提案中，我们 目前的候选生物标志物SV-VCID，将有助于财团。 我们已经确定了3D FLAIR、ASL和DTI的MRI成像模式作为我们的成像候选 生物标志物。我们还鉴定了IL-12 p70、TNFα、PIGF和VEGFD作为我们的候选体液生物标志物， 在我们分析的队列子集中，我们可以很好地区分SVD。在这个应用程序中，我们有一个计划， 开发我们的候选生物标志物，并通过UH 2阶段验证它们， 并通过UH 3部分作为联合体的成员。此外，我们还具有显著的优势， 将有助于协同作用，并推动整个财团在我们的共同目标，发展生物标志物 准备在联盟的第6-7年进行大规模临床试验和FDA认证。这些 优势包括通过我们的ADC和其他NIH倡议支持的特征良好的纵向队列， 我们长期以来积极参与财团，提供所需的经验和基础设施， 确保UH 2/UH 3机制的成功，我们的数据共享历史，包括样本在内的资源共享， 招募研究参与者进行纵向研究，以及我们在基础和翻译方面的基础 科学

Abstract Vascular contributions to cognitive impairment and dementia (VCID) describes cognitive impairment resulting from cerebrovascular disease or dysfunction. VCID is a frequent co-morbidity with Alzheimer's disease (AD), as well as a single dementia-causing entity. The most common vasculopathy associated with cognitive impairment is cerebral small vessel disease (SVD). It is highly likely that SVD significantly contributes to the clinical manifestation of dementia, and therefore is a viable target for disease-modifying therapies, whether alone or in combination with AD-targeting therapies. One major obstacle for therapeutic development is the lack of biomarkers that are predictive of the presence and course of SVD-VCID. In this proposal we present candidate biomarkers for SV-VCID that will contribute to the consortium. We have identified MRI imaging modalities of 3D FLAIR, ASL, and DTI as our imaging candidate biomarkers. We have also identified IL-12 p70, TNFα, PIGF and VEGFD as our candidate fluid biomarkers that discriminate SVD well in the subset of our cohort that we have analyzed. In this application we have a plan for developing our candidate biomarkers and validating them through the UH2 phase an individual research group, and also through the UH3 part as a member of the consortium. In addition, we bring significant strengths that will help synergize and move the consortium as a whole forward in our collective goal of developing biomarkers that are ready for large scale clinical trials and FDA qualification in years 6-7 of the consortium. These strengths include a well characterized, longitudinal cohort supported through our ADC and other NIH initiatives, our long history of active participation in consortia providing the experience and infrastructure needed to ensure success in this UH2/UH3 mechanism, our history of data sharing, resource sharing including samples, recruitment of research participants for longitudinal studies, and our foundation in basic and translational science.