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

摘要 血管对认知损害和痴呆的贡献(VCID)描述认知损害 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共病 疾病(AD)，以及单一的导致痴呆症的实体。与以下疾病相关的最常见的血管病变 认知障碍是一种脑部小血管疾病。奇异值分解极有可能对 痴呆症的临床表现，因此是疾病修正疗法的可行靶点， 无论是单独使用还是与AD靶向治疗相结合。治疗发展的一个主要障碍 缺乏能够预测SVD-VCID的存在和进程的生物标志物。在这份提案中，我们 提出SV-VCID的候选生物标志物，这些生物标志物将为财团做出贡献。 我们已经确定了3D FLAIR、ASL和DTI的MRI成像方式作为我们的候选成像方式 生物标志物。我们还确定了IL-12p70、肿瘤坏死因子α、前列腺素F和血管内皮生长因子作为我们的候选流体生物标志物。 在我们分析的队列的子集中，SVD被很好地区分开来。在此应用程序中，我们有一个计划 开发我们的候选生物标记物，并通过个人研究小组的UH2阶段验证它们， 也通过作为财团成员的UH3部分。此外，我们还带来了显著的优势 将有助于协同作用并推动整个财团在我们开发生物标记物的集体目标方面取得进展 准备好在财团的6-7年进行大规模临床试验和FDA资格。这些 优势包括通过我们的ADC和其他NIH倡议支持的具有良好特征的纵向队列， 我们积极参与财团的悠久历史，提供了所需的经验和基础设施 确保UH2/UH3机制的成功，确保我们的数据共享、资源共享(包括样本)、 招募纵向研究的研究参与者，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.