Cerebral small vessel disease: Enhancing the diagnostic precision of MRI

脑小血管疾病：提高 MRI 的诊断精度

• 批准号: 8226423
• 负责人: LARY C WALKER
• 金额: $ 25.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226423
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Amyloid; Animal Model; Archives; Autopsy; Awareness; Biological Markers; Blood; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrum; Characteristics; Cognition; Data; Dementia; Detection; Diabetic Angiopathies; Diagnosis; Diagnostic; Disease; Elderly; Foundations; Functional disorder; Future; Goals; Healthcare; Histologic; Human; Image; Impaired cognition; Individual; Infarction; Inflammation; Investigation; Lead; Lesion; Life; Link; Magnetic Resonance Imaging; Modeling; Molecular; Multi-Infarct Dementia; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Population; Primates; Process; Protocols documentation; Research; Research Personnel; Risk; Risk Factors; Role; Saimiri; Sampling; Scanning; Signal Transduction; Smooth Muscle; Societies; Specificity; Staging; System; Therapeutic; Tissue Sample; Vascular Diseases; aged; aging brain; base; cohort; improved; in vivo; neuroimaging; new therapeutic target; nonhuman primate; novel; post stroke; programs; white matter change

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.

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长，血管性认知障碍（VCI）将成为21世纪的重大医疗负担。磁共振成像 (MRI) 的最新进展不断降低检测大脑血管异常的阈值，使人们越来越认识到小血管疾病和微梗塞可能累积导致 VCI。然而，目前 MRI 的能力因无法将异常 MR 信号明确地与特定病变类型联系起来而受到限制。有效的动物模型将极大地加速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 Aβ 肽在脑血管壁中积聚。研究人员越来越多地采用新颖的成像方案来非侵入性地分析 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数据的信息。老年松鼠猴是自然发生的 CAA 的独特动物模型，与人类的疾病高度相似。我们研究项目的总体目标是阐明 CAA 在老年人血管功能障碍和认知能力下降中的作用。该提案的目的是利用这种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中与 CAA 相关的病变。为了实现这一目标，我们首先将在强大的 (7T) MRI 扫描仪中研究来自患有 CAA 的老年松鼠猴的独特大脑存档样本，以及来自患有 CAA 的人类的死后组织样本。这样，我们就可以在最佳条件下检测出多种血管病变。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老年松鼠猴进行体内成像。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相关。这种新型灵长类动物模型的研究结果将为未来老年人 CAA 的发病机制、诊断和治疗的非侵入性研究奠定基础。 公共健康相关性：在这项脑淀粉样血管病 (CAA) 的调查中，我们要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病变（包括微梗塞、局灶性炎症和白质变化）相关。我们将通过组织化学分析 7T MRI 扫描仪在老年松鼠猴（其发展出深刻的、类似人类的 CAA）和患有 CAA 的老年人类组织样本中检测到的信号异常来解决这个问题。这项研究的影响在于：1）它将使临床医生能够自信地将活体患者的异常信号与特定病变类型联系起来，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，这将有助于确定新的治疗靶点； 3）它将验证老年松鼠猴作为老年人类微血管疾病的生物学近似动物模型。