Longitudinal validation of cerebral small vessel disease biomarkers in diverse community-based older adults without dementia

摘要 脑小血管疾病(SVD)包括一系列常见的过程和病理(动脉硬化、脑淀粉样血管病变、小血管动脉粥样硬化、微小和微小的梗塞和出血、血管周围间隙扩大和白质疾病)，我们和其他人已经证明与认知障碍和痴呆(VCID)有关。为促进小血管VCID的诊断、预防和治疗，迫切需要高质量的SVD生物标志物。MarkVCID联盟的使命一直是确定SVD最有前景的生物标记物，并进行分析(仪器)验证和初步临床验证。我们在拉什大学医学中心和伊利诺伊理工学院的团队有幸成为这项初步工作的积极参与者。我们现在迫切希望通过这项提案继续这一合作努力。拟议项目的目标是在没有痴呆的不同队列中对MarkVCID选择的生物标记物进行严格的纵向临床验证，并调查这些生物标记物与SVD神经病理指标的关联，与其他联盟站点协同工作，提供科学专业知识、实验基础设施和科学指导。具体地说，我们建议招募、招募和纵向评估一个庞大的、多样化的、以社区为基础的非痴呆症老年人群体，使用MarkVCID临床评估和生物标记物来测试生物标记物与认知功能下降和SVD神经病理指标相关的假设。这将是拉什阿尔茨海默病研究中心的快速记忆和老龄化项目(MAP)、少数民族老龄化研究(MARS)、宗教秩序研究(ROS)、临床核心(CC)和拉丁裔核心(LATC)参与者的嵌套子研究，这些研究是正在进行的纵向、临床-病理队列老龄化研究，招募非痴呆者，并具有高随访率。玛氏和CC只招收非裔美国人，LATC招收拉美裔老年人。我们过去对MarkVCID的贡献支持我们目前的目标。首先，我们证明了我们有能力招募和跟踪一大群不同的非痴呆症老年人，其中一些人已经死亡，这使得尸检研究成为可能。其次，我们开发并公开了一种新的高性能的动脉硬化生物标志物，命名为ARTS，我们使用机器学习对MRI和病理数据进行训练。第三，我们为多个MarkVCID生物标志物的分析和初步临床验证做出了贡献。第四，我们领导了MarkVCID成像生物标记物委员会，并积极参与了该联盟的所有职能。我们建议利用我们的专业知识和基础设施在不同人群中对MarkVCID生物标记物进行严格的纵向临床验证，并调查这些生物标记物与SVD神经病理指标的相关性。

ABSTRACT Cerebral small vessel disease (SVD) encompasses a range of common processes and pathologies (arteriolosclerosis, cerebral amyloid angiopathy, small vessel atherosclerosis, small and microscopic infarcts and bleeds, enlarged perivascular spaces, and white matter disease) that we and others have shown are associated with impaired cognition and dementia (VCID). High-quality biomarkers of SVD are critically needed to advance the diagnosis, prevention, and treatment of small vessel VCID. The mission of the MarkVCID consortium has been to identify the most promising biomarkers of SVD and conduct analytical (instrumental) validation and preliminary clinical validation. Our team at Rush University Medical Center and Illinois Institute of Technology was privileged to be active participants in this initial work. We are now eager to continue this collaborative effort with this proposal. The objective of the proposed project is to conduct rigorous longitudinal clinical validation of MarkVCID-selected biomarkers in a diverse cohort free of dementia, and to investigate the associations of these biomarkers with SVD neuropathologic indices, working synergistically with other consortium sites and contributing scientific expertise, experimental infrastructure, and scientific guidance. Specifically, we propose to recruit, enroll, and longitudinally assess a large, diverse, community-based group of older adults without dementia using MarkVCID clinical evaluation and biomarkers, to test the hypotheses that the biomarkers are associated with cognitive decline and SVD neuropathologic indices. This will be a nested sub-study of participants of the Rush Memory and Aging Project (MAP), Minority Aging Research Study (MARS), Religious Orders Study (ROS), Clinical Core (CC), and Latino Core (LATC) of the Rush Alzheimer’s Disease Research Center, which are on-going longitudinal, clinical-pathologic cohort studies of aging that recruit non-demented individuals and have high follow-up rates. MARS and CC recruit exclusively African Americans, and LATC recruits Latino older adults. Our past contributions to MarkVCID support our current aims. First, we demonstrated our ability to recruit and follow a large and diverse group of non-demented older adults, some of whom died, enabling autopsy studies. Second, we developed and made publicly available a novel biomarker of arteriolosclerosis with high performance, named ARTS, which we trained using machine learning on MRI and pathology data. Third, we contributed to the analytical and initial clinical validation of multiple MarkVCID biomarkers. Fourth, we led the MarkVCID imaging biomarkers committee and were active in all functions of the consortium. We propose to leverage our expertise and infrastructure to conduct rigorous longitudinal clinical validation of MarkVCID biomarkers in a diverse population, and to investigate the associations of these biomarkers with SVD neuropathologic indices.