Multiethnic Validation of VCID biomarkers in South Texas

摘要 脑部小血管疾病(CSVD)是全球痴呆症负担的重要组成部分。由于血管疾病既可以预防，也可以安全治疗，因此干预措施有很大的潜力来减轻痴呆症的负担。然而，需要更多的研究来开发合适的脑小血管对认知障碍和痴呆(VCID)的贡献的生物标志物。美国国家神经疾病和中风研究所(NINDS)支持MarkVCID倡议，在七个地点和一个协调中心推进VCID生物标记物的识别和验证。作为一个贡献站点，我们的团队领导了两个候选生物标记物的开发，帮助定义和协调所有方案，并加入了多站点验证，从单个站点招募了最大的西班牙裔样本。在这项提案中，我们寻求包括整个南得克萨斯州的更多样化的人口，包括来自休斯顿和圣安东尼奥的西班牙裔和非裔美国人，中风和痴呆症诊所，初级保健和人口研究。我们进一步建议在基因组流行病学心脏和衰老研究(CHARD)联盟的四个队列的丰富数据集中对候选生物标记物进行额外的验证，这些队列具有遗留数据(MRI、痴呆)和生物标本(血浆、血清、脑尸检)。作为MarkVCID网站，我们的目标是在不同的样本中对CSVD的候选生物标记物进行全面、纵向的验证。我们的目标是招募400名55岁以上有主观认知主诉、轻度认知障碍或推测为血管病因的早期痴呆的参与者，并在5年内保留至少320人；~60人将出现在UH3阶段，并将有7年的随访。我们将按照MarkVCID联盟UH2/UH3阶段开发的方案进行全面检查，以收集病史、生物标本(血液、脑脊液)、成像(MRI具有脑血管反应性、光学相干断层扫描血管成像)和神经心理数据(认知、CDR)。我们将通过临时电话筛查进行后续检查，以了解认知状态，并通过共识会议持续监测痴呆症。此外，我们将向同意的参与者提供脑部尸检，以评估VCID生物标记物的临床病理相关性。我们将按照既定的试剂盒方案测量选定的液体和成像生物标记物，并根据其预先指定的假设对生物标记物进行纵向临床验证。最后，我们将在指控联盟的四个队列中进行额外的验证。数据、生物样品和结果将通过指定的MarkVCID协调中心与财团和外部合格调查人员共享。我们的团队将拥有强大的领导力，拥有UH3 Seshadri，Fornage(多个PI)，Tracy(Co-I)的PI，一个久经考验的年轻Co-I现在接替Contact PI(Satizabal)，并增加了一位出色的中风试验负责人(Savitz)。

ABSTRACT Cerebral small vessel disease (CSVD) contributes considerably to the global burden of dementia. As vascular diseases can be both prevented and safely treated, there is a great potential for interventions to reduce the burden of dementia. However, more research is needed to develop suitable biomarkers of cerebral small vessel contributions to cognitive impairment and dementia (VCID). The National Institute of Neurological Disorders and Stroke (NINDS) has supported the MarkVCID initiative to advance the identification and validation of biomarkers for VCID across seven sites and a coordinating center. As one contributing site, our team has led the development of two candidate biomarkers, helped define and harmonize all protocols, and joined multisite validation with the recruitment of the largest Hispanic sample from a single site. In this proposal, we seek to include a more diverse population across South Texas, including Hispanic and African Americans, from Houston and San Antonio, stroke and dementia clinics, primary care, and population studies. We further propose additional validation of candidate biomarkers in the rich datasets of four cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium that have legacy data (MRI, dementia) and biospecimens (plasma, serum, brain autopsy). As a MarkVCID site, we aim to perform a comprehensive, longitudinal validation of candidate biomarkers of CSVD in a diverse sample. We aim to recruit 400 participants over age 55 years with subjective cognitive complaints, mild cognitive impairment, or early dementia of presumed vascular etiology and retain at least 320 of them over the 5-year follow-up; ~60 will be persons seen in the UH3 phase and will have 7 years of follow- up. We will perform a comprehensive examination to collect medical history, biospecimens (blood, CSF), imaging (MRI with cerebrovascular reactivity, optical coherence tomography angiography), and neuropsychological data (cognition, CDR) following the protocols developed during the UH2/UH3 phases of the MarkVCID consortium. We will perform a follow-up examination with interim phone screenings for cognitive status and continuous dementia surveillance via consensus conferences. Further, we will offer brain autopsies to consenting participants for the assessment of clinicopathological correlates of VCID biomarkers. We will measure selected fluid and imaging biomarkers following established kit protocols and perform longitudinal clinical validation of biomarkers according to their pre-specified hypotheses. Finally, we will perform additional validation in four cohorts of the CHARGE consortium. Data, biospecimens, and results will be shared with the consortium and external qualified investigators through the designated MarkVCID coordinating center. Our team will have strong leadership with the PIs of the UH3 Seshadri, Fornage (multiple PI), Tracy (Co-I), a proven, young Co-I now taking over as Contact PI (Satizabal), and the addition of an exceptional stroke trials leader (Savitz).