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: 9281630
• 负责人: Anand Viswanathan
• 金额: $ 70.87万
• 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/9281630
• 关键词: Alzheimer' s Disease; Amyloid Proteins; Amyloid beta-Protein; Amyloid deposition; Area; Arteries; Biological Markers; Blood Vessels; Brain; Brain hemorrhage; Brain region; Cerebral Amyloid Angiopathy; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical; Cognitive; Collaborations; Communities; Data; Dementia; Deposition; Development; Disease; Elderly; Evaluation; Exhibits; Future; Hemorrhage; Image; Impaired cognition; Individual; Infarction; Laboratories; Lead; Lesion; Ligands; Lobar; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Neurobehavioral Manifestations; Neurologic Examination; Neuropsychology; Pathologic; Pathology; Patients; Pattern; Pittsburgh Compound-B; Play; Positron-Emission Tomography; Research Personnel; Risk Factors; Role; Scanning; Severities; Siderosis; Specificity; Subarachnoid Space; Subgroup; Techniques; Therapeutic; Therapeutic Trials; Time; Vascular Cognitive Impairment; White Matter Hyperintensity; abeta accumulation; abeta deposition; age related; base; cerebral microinfarct; cognitive testing; design; executive function; follow-up; in vivo; insight; mild cognitive impairment; neuroimaging; neuroimaging marker; non-demented; population based; prevent; processing speed; profiles in patients; public health relevance; 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(申请人提供)：脑淀粉样血管病(CAA)是一种与年龄相关的脑小血管疾病，是老年人脑叶出血(ICH)和血管认知障碍的常见原因。它的特点是皮质和软脑膜动脉壁中进行性沉积的β-淀粉样蛋白(A？)。虽然CAA是公认的脑叶脑出血的病因，但神经病理学研究表明，较轻形式的CAA在老年人中更为常见。在没有脑出血的非痴呆者中，近14%的人患有中到重度的CAA，超过50%的人至少有轻度的CAA，这些CAA独立地导致认知障碍。基于这些数据，可以想象CAA可能在很大一部分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。我们的初步数据表明，即使在没有脑出血的情况下，严格意义上的叶MB对CAA也有很高的特异性，因此现在可以很容易地识别出患有早期CAA的个体。然而，一个重要的悬而未决的问题是，哪些额外的血管病变使这些人容易出现认知症状，以及阿尔茨海默病(AD)的病理在认知障碍中扮演着什么角色。事实上，除了MB，其他神经成像和实验室生物标记物似乎与血管Aü蓄积有关。脑白质血管周围间隙扩张(DPVS)(新近发现的脑小血管疾病的重要标志)、蛛网膜下腔慢性出血(称为浅表铁质沉着症)和脑白质高信号的后方分布(慢性脑缺血的标志)都与晚期CAA有关。这可能与后脑区域血管淀粉样蛋白沉积增加有关-有证据表明，匹兹堡化合物B(PIB)在CAA患者的枕骨相对负荷增加，这是一种检测体内纤维和血管淀粉样蛋白沉积的PET配体。CAA患者还被证明脑脊液(CSF)中40种淀粉样蛋白缺乏。最后，病理上的脑微梗塞在CAA中似乎非常常见。目前的应用旨在研究Aü介导的血管病理在老年人认知症状中的作用。支持这一建议的关键问题是：1)是否有神经影像和实验室生物标志物的特征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患者轻度认知症状不同的特殊神经心理特征？3)导致早期CAA患者认知功能下降的易感危险因素有哪些？