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

项目摘要/摘要 脑部小血管疾病(SVD)所致的血管认知障碍(VCI)是目前公认的 2016美国国立卫生研究院阿尔茨海默病相关痴呆症峰会证明的公共卫生问题 建议。尽管单个神经成像生物标记物，如脑微出血(MB)或白色 物质高信号(WMH)常用于小血管VCI的诊断和监测 疾病，没有单一的神经影像生物标志物出现作为小血管VCI的有效替代标志物 审判。这可能是因为仍不确定是否有任何单一的生物标志物对认知产生更强烈的影响 与其他病变相比，或者这些病变是否有累积效应。最近出现的强有力的证据 提示新的扩散张量成像(DTI)方法可以可靠地捕捉到 不同SVD病变的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 VCI试验中极有希望的候选生物标记物。这项建议的目的是利用油井- 特征性小血管病变脑淀粉样血管病(CAA)通过以下方法验证DTI作为SVD生物标志物的有效性 确定1)DTI与认知损害的关联，独立于其他成像参数，以及2) DTI的潜在生物机制。CAA是一种与年龄相关的SVD，是小血管VCI的常见原因 其特征是皮质和软脑膜壁中β-淀粉样蛋白(Aβ)的进行性沉积 细小的动脉。神经病理学证据表明，CAA对痴呆的作用独立于其他因素 与年龄相关的神经病理，包括阿尔茨海默病(AD)。小细胞肺癌的所有个体生物标记物 血管VCI可见于CAA，包括MB和WMH。此外，尸检研究表明，大脑 微梗塞(CMI)是小血管VCI的一个重要特征，在CAA中较为常见。CAA也与 DTI的改变似乎与执行功能和执行功能等临床重要指标相关 处理速度。CAA是一种理想的小血管VCI模型。目前的建议首先旨在 显示基于DTI的生物标记物强烈跟踪CAA的认知变化。其次，它的目的是建立 这些生物标记物的组织病理学基础，以便产生生物验证的生物标记物 CAA和小血管VCI的临床试验。成功完成拟议的目标具有很大的潜力 阐明CAA中DTI异常的机制基础，并将导致基于试验的DTI 小血管VCI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时，在确定要针对的组织损伤机制时至关重要 适用于小型船舶VCI。拟议的分析旨在建立一座从神经功能到活体的完整桥梁 DTI，体外DTI，并最终达到黄金标准的神经病理学。虽然这些研究涉及CAA，但我们 预计这种基于DTI的生物标记物将广泛适用于许多类型的小血管VCI 在诊所里。

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.