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

不同社区无痴呆老年人脑小血管疾病生物标志物的纵向验证

• 批准号: 10608782
• 负责人: Konstantinos Arfanakis
• 金额: $ 118.44万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608782
• 关键词: Longitudinal; validation; cerebral; small; vessel

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.

摘要 脑小血管病（SVD）包括一系列常见的过程和病理（小动脉硬化、脑淀粉样血管病、小血管动脉粥样硬化、小和显微镜下梗死和出血、血管周围间隙扩大和白色疾病），我们和其他人已经证明这些过程和病理与认知受损和痴呆（VCID）相关。迫切需要高质量的SVD生物标志物来推进小血管VCID的诊断、预防和治疗。MarkVCID联盟的使命是确定最有希望的SVD生物标志物，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积极参与了这项初步工作。我们现在渴望继续这一合作努力，提出这一建议。拟议项目的目标是在无痴呆的多样化队列中对MarkVCID选择的生物标志物进行严格的纵向临床验证，并研究这些生物标志物与SVD神经病理学指标的相关性，与其他联盟网站协同工作，并提供科学专业知识，实验基础设施和科学指导。具体来说，我们建议招募，登记，并纵向评估一个大型的，多样化的，以社区为基础的老年人群体没有痴呆症使用MarkVCID临床评价和生物标志物，以测试的假设，生物标志物与认知能力下降和SVD神经病理指标。这将是一项嵌套的子研究，参与者包括拉什记忆和衰老项目（MAP）、少数民族衰老研究（MARS）、宗教秩序研究（ROS）、临床核心（CC）和拉什阿尔茨海默病研究中心的拉丁裔核心（LATC），这些研究是正在进行的纵向、临床病理学队列研究，招募非痴呆个体，随访率高。MARS和CC只招募非洲裔美国人，LATC招募拉丁裔老年人。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个庞大而多样化的非痴呆老年人群体，其中一些人已经死亡，从而能够进行尸检研究。其次，我们开发并公开了一种高性能的小动脉硬化症新生物标志物，名为ARTS，我们使用机器学习对MRI和病理学数据进行训练。第三，我们为多种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成像生物标志物委员会，并积极参与该联盟的所有职能。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生物标志物进行严格的纵向临床验证，并研究这些生物标志物与SVD神经病理学指标的相关性。