Cerebral small vessel disease: Enhancing the diagnostic precision of MRI

描述（由申请人提供）：脑血管疾病是老年人痴呆的最常见原因之一。随着西方社会老年人口的不断增加，血管性认知障碍（VCI）将成为21世纪重要的医疗负担。磁共振成像（MRI）的最新进展不断降低检测脑血管异常的阈值，使人们越来越意识到小血管疾病和微梗死可累积导致VCI。然而，目前MRI的能力受到限制，无法将异常的MR信号明确地与特定的病变类型联系起来。有效的动物模型将大大加快脑血管疾病的诊断和治疗。在研究脑a -淀粉样血管病（CAA）时，明确识别MR异常一直是一个特别的问题，CAA是一种老年人的疾病，其中错误折叠的a -肽积聚在脑血管壁上。研究人员越来越多地采用新的成像方案来无创分析CAA。然而，迫切需要能够解释CAA和其他血管疾病患者神经影像学数据的信息。年老的松鼠猴是一种独特的动物模型，自然发生的CAA与人类的疾病高度相似。我们研究项目的首要目标是阐明CAA在老年人血管功能障碍和认知能力下降中的作用。本提案的目的是利用这种特殊的灵长类动物模型来优化MRI在活体患者中非侵入性识别和表征caa相关病变的能力。为了实现这一目标，我们首先将在强大的（7T） MRI扫描仪中研究患有CAA的老年松鼠猴存档的独特大脑样本，以及患有CAA的人类的死后组织样本。这样，我们可以在最佳条件下检测到各种血管病变。接下来，我们将利用从这些离体成像研究中获得的信息对一小群体内的老年松鼠猴进行成像。然后将对大脑进行显微镜检查，以明确识别和表征MRI异常，并确定病变的细胞和分子特征。我们预测MRI信号异常将与CAA和相关病变的特定组织病理学指标有关。这一新的灵长类动物模型的发现将为未来对老年人CAA发病机制、诊断和治疗的非侵入性研究奠定基础。

DESCRIPTION (provided by applicant): Cerebrovascular disease is one of the most common causes of dementia in aging humans. With the growing elderly population in Western societies, vascular cognitive impairment (VCI) will become a significant healthcare burden in the 21st century. Recent advances in magnetic resonance imaging (MRI) are continually lowering the threshold for detection of vascular anomalies in the brain, leading to a growing awareness that small vessel disease and microinfarcts can cumulatively lead to VCI. However, the power of MRI currently is limited by the inability to link anomalous MR signals unambiguously to specific lesion types. Valid animal models would greatly accelerate diagnostic and therapeutic approaches to cerebrovascular disease. The explicit identification of MR anomalies has been a particular problem in investigating cerebral A¿-amyloid angiopathy (CAA), a disease of the elderly in which misfolded A¿ peptide accumulates in the walls of brain blood vessels. Investigators have increasingly employed novel imaging protocols to analyze CAA non-invasively. However, there is a critical need for information that will enable the interpretation of neuroimaging data on CAA and other vascular disorders in patients. The aged squirrel monkey is a unique animal model of naturally occurring CAA that is highly similar to the disorder in humans. The overarching goal of our research program is to clarify the role of CAA in vascular dysfunction and cognitive decline in the elderly. The objective of this proposal is to employ this exceptional primate model to optimize the power of MRI to non-invasively identify and characterize CAA-related lesions in living patients. To achieve this goal, we first will investigate a unique sample of archived brains from aged squirrel monkeys with CAA, along with postmortem tissue samples from humans with CAA, in a powerful (7T) MRI scanner. In this way, we can detect a variety of vascular lesions under optimal conditions. Next, we will use the information gained from these ex vivo imaging studies to image a small cohort of aged squirrel monkeys in vivo. The brains then will be examined microscopically to identify and characterize the MRI anomalies unambiguously, and to determine the cellular and molecular features of the lesions. We predict that MRI signal anomalies will be linked to specific histopathological indicators of CAA and associated lesions. The findings from this novel primate model will establish a foundation for future non-invasive studies of the pathogenesis, diagnosis and treatment of CAA in aged humans. PUBLIC HEALTH RELEVANCE: In this investigation of cerebral amyloid angiopathy (CAA), the key question that we will address is whether anomalies detected by high field MRI can be unambiguously linked to specific lesions, including microinfarcts, focal inflammation, and white matter changes. We will approach this question by analyzing histochemically the signal anomalies detected in a 7T MRI scanner in aged squirrel monkeys (which develop profound, human-like CAA) and in tissue samples from aged humans with CAA. The impact of this research is that 1) it will enable clinicians to confidently link anomalous signals in living patients to specific lesion types, improving diagnostic precision and thus simplifying therapeutic decisions; 2) it will provide information on the cellular and molecular features of microvascular lesions that will help to identify new therapeutic targets; and 3) it will validate the aged squirrel monkey as a biologically proximate animal model of microvascular disease in aging humans.