Cerebral small vessel disease: Enhancing the diagnostic precision of MRI

描述(申请人提供)：脑血管疾病是导致老年人痴呆的最常见原因之一。随着西方社会老年人口的增长，血管认知障碍(VCI)将成为21世纪的重大医疗负担。磁共振成像(MRI)的最新进展正在不断降低检测大脑中血管异常的门槛，导致人们越来越意识到小血管疾病和微梗塞可以累积导致VCI。然而，目前MRI的能力受到限制，因为无法明确地将异常MR信号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方法。明确识别MR异常一直是研究脑Aβ-淀粉样血管病(CAA)的一个特殊问题，CAA是一种老年人疾病，错误折叠的A‘肽聚集在脑血管壁中。研究人员越来越多地使用新的成像技术来非侵入性地分析CAA。然而，迫切需要能够解释患者CAA和其他血管疾病的神经影像数据的信息。老年松鼠猴是一种独特的自然发生的CAA的动物模型，与人类的CAA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功能下降中的作用。这项建议的目的是利用这一特殊的灵长类动物模型来优化MRI的能力，以非侵入性地识别和表征活体患者的CAA相关病变。为了实现这一目标，我们首先将在一台强大的(7T)磁共振扫描仪中，研究患有CAA的老年松鼠猴子的独特大脑存档样本，以及患有CAA的人类的死后组织样本。通过这种方式，我们可以在最佳条件下检测各种血管病变。接下来，我们将使用从这些体外成像研究中获得的信息，在体内对一小群老年松鼠猴子进行成像。然后，将对大脑进行显微镜检查，以明确地识别和描述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及其相关病变的特定组织病理学指标相关联。这一新的灵长类动物模型的发现将为未来非侵入性研究老年人CAA的发病机制、诊断和治疗奠定基础。 公共卫生相关性：在这项脑淀粉样血管病(CAA)的调查中，我们将解决的关键问题是，高场MRI检测到的异常是否可以明确地与特定的病变联系起来，包括微梗塞、局灶性炎症和脑白质变化。我们将通过组织化学方法分析在7T MRI扫描仪中检测到的信号异常，这些信号异常发生在老年松鼠猴子(发生严重的、类似人类的CAA)和患有CAA的老年人类组织样本中。这项研究的影响是：1)它将使临床医生能够自信地将活着患者的异常信号与特定的病变类型联系起来，提高诊断精度，从而简化治疗决策；2)它将提供有关微血管病变的细胞和分子特征的信息，有助于确定新的治疗靶点；3)它将验证老年松鼠猴在生物学上是老年人类微血管疾病的动物模型。

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.