Vascular Pathology in Early and Asymptomatic Cerebral Amyloid Angiopathy

早期和无症状脑淀粉样血管病的血管病理学

• 批准号: 8929119
• 负责人: Anand Viswanathan
• 金额: $ 68.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929119
• 关键词: Alzheimer' s Disease; Amyloid; Amyloid Proteins; Amyloid deposition; Area; Arteries; Biological Markers; Blood Vessels; Brain; Brain hemorrhage; Brain region; Cerebral Amyloid Angiopathy; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical; Collaborations; Communities; Data; Dementia; Deposition; Development; Disease; Elderly; Evaluation; Exhibits; Future; Health; Hemorrhage; Image; Impaired cognition; Individual; Infarction; Laboratories; Lead; Lesion; Life; Ligands; Lobar; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Microvascular Dysfunction; Neurobehavioral Manifestations; Neurologic Examination; Pathology; Patients; Pattern; Pittsburgh Compound-B; Play; Positron-Emission Tomography; Relative (related person); Research Personnel; Risk Factors; Role; Scanning; Severities; Siderosis; Specificity; Staging; Subarachnoid Space; Subgroup; Techniques; Therapeutic; Therapeutic Trials; Time; Vascular Cognitive Impairment; White Matter Hyperintensity; age related; base; cognitive testing; design; executive function; follow-up; in vivo; insight; mild cognitive impairment; neuroimaging; neuropsychological; population based; prevent; processing speed; tau Proteins; white matter

DESCRIPTION (provided by applicant): Cerebral amyloid angiopathy(CAA) is an age-related cerebral small vessel disease that is a common cause of lobar intracerebral hemorrhage (ICH) and vascular cognitive impairment in the elderly. It is characterized by progressive deposition of ß-amyloid (Aß) in the walls of cortical and leptomeningeal arteries. Although CAA is a widely recognized cause of lobar ICH, neuropathological studies suggest that milder forms of CAA are far more common in the elderly. In non-demented individuals without ICH, nearly 14% have moderate to severe CAA and greater than 50% have at least mild degrees of CAA that independently contributes to cognitive impairment. Based on these data, it is conceivable that CAA may play an important role in a large percentage of individuals with subtle cognitive symptoms or mild cognitive impairment (MCI). As our preliminary data suggest that strictly lobar MB have high specificity for CAA even in the absence of ICH, individuals with early CAA may be now readily identified. However, an important unanswered question is what additional vascular lesions predispose these individuals to develop cognitive symptoms and what role Alzheimer's disease (AD) pathology plays in cognitive impairment. Indeed, beyond MB, other neuroimaging and laboratory biomarkers appear be associated with vascular Aß accumulation. Dilated perivascular spaces (DPVS) in the white matter (a recently identified important marker of cerebral small vessel disease), chronic bleeding in the subarachnoid space (known as superficial siderosis) and posterior distribution of white matter hyperintensities (a marker of chronic cerebral ischemia) have all been associated with advanced CAA. This is likely related to increased vascular amyloid deposition in posterior brain regions-supported by evidence showing elevated relative occipital burden of Pittsburgh Compound B (PiB) in patients with CAA, the PET ligand that detects fibrillar and vascular amyloid deposition in vivo. Patients with CAA have also been shown to have depletion of the Aß40 species of amyloid protein in cerebrospinal fluid (CSF). Finally, cerebral microinfarctions on pathology appear to be very common in CAA. The current application aims to examine the role of Aß-mediated vascular pathology in cognitive symptoms in the elderly. The key questions motivating this proposal are: 1) Is there a signature of neuroimaging and laboratory biomarkers that can reliably identify patients with early CAA? 2) Do patients early CAA have a particular neuropsychological profile distinct from patients with mild cognitive symptoms due to early AD? and 3) What are the predisposing risk factors that lead to cognitive decline in patients with early CAA?

描述（由申请方提供）：脑淀粉样血管病（CAA）是一种与年龄相关的脑小血管疾病，是老年人脑叶内出血（ICH）和血管性认知障碍的常见原因。其特征在于皮质和软脑膜动脉壁中β-淀粉样蛋白（AAPs）的进行性沉积。虽然CAA是脑叶性脑出血的一个公认原因，但神经病理学研究表明，轻度CAA在老年人中更为常见。在没有ICH的非痴呆个体中，近14%的人患有中度至重度CAA，超过50%的人患有至少轻度的CAA，这些CAA独立地导致认知障碍。基于这些数据，可以想象CAA可能在大部分具有轻微认知症状或轻度认知障碍（MCI）的个体中发挥重要作用。由于我们的初步数据表明，即使在没有ICH的情况下，严格的脑叶MB对CAA也具有高特异性，因此现在可以很容易地识别早期CAA患者。然而，一个重要的未回答的问题是什么额外的血管病变易使这些人发展认知症状和阿尔茨海默病（AD）病理学在认知障碍中起什么作用。事实上，除了MB之外，其他神经影像学和实验室生物标志物似乎与血管中的血管炎性细胞聚集有关。白色物质中的血管周围空间（DPVS）扩张（最近发现的脑小血管疾病的重要标志物）、蛛网膜下腔慢性出血（称为浅表铁质沉着症）和白色物质高信号（慢性脑缺血的标志物）的后部分布均与晚期CAA相关。这可能与后脑区域血管淀粉样蛋白沉积增加有关-证据表明CAA患者中匹兹堡化合物B（Pi B）的相对枕骨负荷升高，PET配体可检测体内纤维和血管淀粉样蛋白沉积。CAA患者还显示出脑脊液（CSF）中淀粉样蛋白A β 40种类的耗竭。最后，病理学上的脑微梗塞在CAA中似乎是非常常见的。本申请旨在检查Ablation介导的血管病理学在老年人认知症状中的作用。激发这一提议的关键问题是：1）是否有神经影像学和实验室生物标志物的签名，可以可靠地识别早期CAA患者？2)早期CAA患者是否具有与早期AD所致轻度认知症状患者不同的特殊神经心理学特征？（3）导致早期CAA患者认知功能下降的易感危险因素是什么？