Validation of Small-Vessel Disease Neuroimaging Biomarkers in Cerebral Amyloid Angiopathy-Related Cognitive Decline

脑淀粉样血管病相关认知衰退中小血管疾病神经影像生物标志物的验证

• 批准号: 9973193
• 负责人: Anand Viswanathan
• 金额: $ 68.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973193
• 关键词: Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-42; Amyloid beta-Protein; Arteries; Autopsy; Axon; Biological; Biological Markers; Biology; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrovascular Trauma; Cerebrum; Clinic; Clinical; Clinical Trials; Cognition; Dementia; Diagnosis; Diffuse; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Foundations; Functional disorder; Funding; Future; Gold; Histology; Image; Impaired cognition; Impairment; Individual; Injury; Intervention; Lead; Lesion; Magnetic Resonance Imaging; Measures; Methods; Microscope; Microscopic; Microvascular Dysfunction; Modeling; Monitor; Myelin; Nervous System Physiology; Neurobehavioral Manifestations; Oligodendroglia; Patients; Public Health; Recommendation; Skeleton; Surrogate Markers; Techniques; Testing; Time; United States National Institutes of Health; Validation; Vascular Cognitive Impairment; White Matter Hyperintensity; Width; Work; abeta deposition; age related; base; biomarker validation; burden of illness; candidate marker; cerebral microbleeds; cognitive change; cohort; density; effective therapy; executive function; imaging biomarker; in vivo; insight; neuroimaging marker; neuropathology; processing speed; symposium; tau Proteins; tissue injury; tool; trial design; vascular injury; white matter

PROJECT SUMMARY/ABSTRACT Vascular cognitive impairment (VCI) due to cerebral small vessel disease (SVD) is now recognized as a key public health issue evidenced by the 2016 NIH Alzheimer's Disease-Related Dementias Summit recommendations. Although individual neuroimaging biomarkers such as cerebral microbleeds (MB) or white matter hyperintensities (WMH) are often used in the diagnosis and monitoring of VCI due to small vessel disease, no single neuroimaging biomarker has emerged as a valid surrogate marker for small vessel VCI trials. This may be because it remains uncertain if any single biomarker more strongly impacts cognition compared to the others or if there is a cumulative effect of these lesions. Recent emerging evidence strongly suggests that new diffusion tensor imaging (DTI) measures can reliably capture the cumulative effect of different SVD lesions in patients with various forms small vessel VCI. These DTI-based biomarkers are thus highly promising candidate biomarkers for VCI trials. The purpose of this proposal is to use the well- characterized small vessel disease cerebral amyloid angiopathy (CAA) to validate DTI as a SVD biomarker by determining 1) DTI's association with cognitive impairment independent of other imaging parameters, and 2) DTI's underlying biologic mechanism. CAA is an age-related SVD that is a common cause of small vessel VCI and is characterized by progressive deposition of β-amyloid (Aβ) in the wall of cortical and leptomeningeal small arteries. Neuropathological evidence suggests that CAA contributes to dementia independent of other age-related neuropathologies, including Alzheimer's disease (AD). All of the individual biomarkers of small vessel VCI are seen in CAA, including MB and WMH. Additionally, autopsy studies suggest that cerebral microinfarctions (CMI), an important feature of small vessel VCI, are common in CAA. CAA is also associated with DTI changes that appear to correlate with clinically important measures like executive function and processing speed. CAA thus represents an ideal model of small vessel VCI. The current proposal first aims to show that DTI-based biomarkers strongly track cognitive change in CAA. Secondly, it aims to establish the histopathologic basis of these biomarkers in order to produce a biologically validated biomarker for use in clinical trials in CAA and small vessel VCI. Successful conclusion of the proposed aims has high potential for elucidating the mechanistic basis of DTI abnormalities in CAA and would result in a trial-ready DTI-based biomarker for potential candidate treatments in small vessel VCI. Insights gained from these studies will also be critical in defining the tissue injury mechanisms to be targeted when selecting future candidate treatments for small vessel VCI. The proposed analyses aim to build a complete bridge from neurologic function to in vivo DTI, ex vivo DTI, and ultimately to gold-standard neuropathology. While these studies involve CAA, we anticipate that this DTI-based biomarker would be broadly applicable to many types of small vessel VCI seen in the clinic.

项目总结/摘要 脑小血管病（SVD）引起的血管性认知功能障碍（VCI）目前被认为是治疗脑血管病的关键。 2016年NIH阿尔茨海默病相关痴呆症峰会证明了这一公共卫生问题 建议.虽然个别神经影像学生物标志物，如脑微出血（MB）或白色 由于血管狭窄，高信号常用于VCI的诊断和监测 疾病，没有单一的神经影像学生物标志物作为小血管VCI的有效替代标志物 审判这可能是因为它仍然不确定是否有任何单一的生物标志物更强烈地影响认知 或者这些病变是否存在累积效应。最近出现的证据有力地表明 新的弥散张量成像（DTI）方法可以可靠地捕获累积效应， 不同SVD病变患者存在不同形式的小血管VCI。因此，这些基于DTI的生物标志物是 非常有希望的候选生物标志物用于VCI试验。这个建议的目的是利用这口井- 特征性小血管疾病脑淀粉样血管病（CAA），以验证DTI作为SVD生物标志物， 确定1）DTI与认知障碍的关联，而不依赖于其他成像参数，以及2） DTI的潜在生物学机制。CAA是一种与年龄相关的SVD，是小血管VCI的常见原因 其特征是β-淀粉样蛋白（Aβ）在皮质和软脑膜壁进行性沉积 小动脉神经病理学证据表明，CAA有助于痴呆独立于其他 与年龄相关的神经病理学，包括阿尔茨海默病（AD）。所有的个体生物标志物小 CAA中可见血管VCI，包括MB和WMH。此外，尸检研究表明， 微梗死（CMI）是小血管VCI的一个重要特征，在CAA中很常见。CAA也与 DTI的变化似乎与执行功能等临床重要指标相关， 处理速度。因此，CAA代表了小血管VCI的理想模型。目前的建议首先旨在 显示基于DTI的生物标志物强烈地追踪CAA中的认知变化。其次，它旨在建立 这些生物标志物的组织病理学基础，以产生生物学验证的生物标志物，用于 CAA和小血管VCI的临床试验。成功实现拟议目标具有很大潜力， 阐明CAA中DTI异常的机制基础，并将导致基于DTI的试验准备 小血管VCI中潜在候选治疗的生物标志物。从这些研究中获得的见解也将 在选择未来的候选治疗方法时， 小血管VCI。拟议的分析旨在建立一个完整的桥梁，从神经功能到体内 DTI，离体DTI，最终达到神经病理学的金标准。虽然这些研究涉及CAA，但我们 我预计这种基于DTI的生物标志物将广泛适用于许多类型的小血管VCI 在诊所里