Validation of Biomarkers of Small Vessel Injury in VCID

该提案是对RFA-NS-21-005的回应，RFA-NS-16-020是RFA-NS-16-020的延续。该项目的总体目标是研究血管疾病对阿尔茨海默病（AD）的影响。小血管疾病是与痴呆相关的主要血管疾病。脑小血管疾病，如小动脉硬化和脑淀粉样血管病，与认知能力下降和血管性认知障碍和痴呆（VCID）的可能性增加独立相关。MarkVCID1联盟共享受试者临床神经心理测试数据、MRI结果和生物样本，以验证生物标志物。美国国立卫生研究院从MarkVCID1中确定了11种可用于未来临床试验的生物标志物。新墨西哥大学在MRI和流体生物标志物方面做出了重大贡献：新墨西哥大学和UCD领导了自由水（FW）生物标志物的工作，并为所有其他MRI生物标志物提供了数据。新墨西哥大学是少数几个收集所有受试者脑脊液（CSF）和匹配血液的中心之一，这有助于选择所有液体生物标志物进入MarkVCID2。我们的团队将CSF和血液样本送到多个地点，以验证血管生成和炎症生物标志物试剂盒，包括CSF胎盘生长因子（PlGF），血液外泌体和内皮炎症试剂盒。我们使用MesoScale Discovery进行流体分析，并且最近购买了Quanterix HD-X单分子分析（SIMOA）仪器，我们将使用它来测量神经丝光（NfL）和PlGF。新墨西哥大学的具体目标是：1)继续领导与UCD合作开发FW生物标志物试剂盒，使该试验做好准备，并将成像数据添加到其他MRI生物标志物试剂盒中；2)继续收集脑脊液和血液样本，为所有脑脊液和血液生物标志物试剂盒的验证做出贡献；3)在两年内招募200名未被充分代表的新患者，以增加传统受试者。UMN预计将获得许多参与者3年的纵向数据。新墨西哥大学有大量的VCID、AD和混合性痴呆患者，以及主观认知投诉，作为两个RO1资助（2006-2016年）和MarkVCID1（2016年至今）的一部分，研究了临床认知测试结果、MRI、CSF和血液数据。这些患者中的许多人都有来自多次随访的纵向数据。新墨西哥大学致力于实现NIH为MarkVCID2制定的目标和里程碑，并为完成生物标志物的评估做出贡献，这些生物标志物将用于血管认知障碍的临床试验。

This proposal is in response to RFA-NS-21-005, which is a continuation of RFA-NS-16-020. The overall goal of the project is to study the impact of vascular disease on Alzheimer’s disease (AD). Small vessel disease is the major vascular disease associated with dementia. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy are independently associated with worse cognitive performance and greater likelihood of vascular cognitive impairment and dementia (VCID). MarkVCID1 consortium shared subject clinical neuropsychological test data, MRI results and biological samples to validate the biomarkers. The NIH identified 11 biomarkers from MarkVCID1 that could be used in future clinical trials. The UNM site made major contributions to both the MRI and fluid biomarkers: UNM and UCD led the work on the Free Water (FW) biomarker, and contributed data to all of the other MRI biomarkers. UNM was one of the few centers that collected cerebrospinal fluid (CSF) and matched blood on all subjects, contributing to all of the fluid biomarkers selected to move into MarkVCID2. Our group contributed CSF and blood samples to multiple sites for validation of the angiogenic and inflammatory biomarker kits, including CSF placental growth factor (PlGF), and blood exosomes and endothelial inflammation kits. We used MesoScale Discovery assays for fluid analysis, and have recently purchased a Quanterix HD-X single molecule assay (SIMOA) instrument that we will use it to measure neurofilament light (NfL) and PlGF. The UNM Specific aims are: 1) to continue to lead to development of the FW biomarker kit in collaboration with UCD to make this trial ready and to add imaging data to the other MRI biomarkers kits; 2) to continue to collect CSF and blood samples to contribute to the validation of all the CSF and blood biomarker kits; and 3) to recruit 200 new underrepresented patients over two years to add to legacy subjects. UMN anticipates to have longitudinal data for 3 years on many participants. UNM has a large number of patients with VCID, AD, and mixed dementias, as well as subjective cognitive complaints that have been studied as part of two RO1 grants (2006-2016) and the MarkVCID1 (2016- present) with data on clinical cognitive test results, MRI, CSF, and blood. Many of these patients have longitudinal data from multiple follow-ups. UNM is committed to achieving the goals and milestones laid out by NIH for MarkVCID2, and to contribute to the completion of the evaluation of the biomarkers that will be used with study-ready cohorts for clinical trials in vascular cognitive impairment.