Vascular Pathology in Early and Asymptomatic Cerebral Amyloid Angiopathy

描述（由申请人提供）：脑淀粉样血管病（CAA）是一种与年龄相关的脑小血管疾病，是老年人脑叶性脑出血（ICH）和血管性认知障碍的常见原因。其特征是ß-淀粉样蛋白（ß）在皮质动脉和小脑膜动脉壁上逐渐沉积。尽管CAA被广泛认为是脑叶性脑出血的原因，但神经病理学研究表明，轻度形式的CAA在老年人中更为常见。在没有脑出血的非痴呆个体中，近14%的人有中度至重度CAA，超过50%的人至少有轻度CAA，单独导致认知障碍。基于这些数据，可以想象CAA可能在很大比例的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，即使在没有脑出血的情况下，严格的大叶性MB对CAA也有很高的特异性，因此现在可以很容易地识别出早期CAA患者。然而，一个重要的未解决的问题是，哪些额外的血管病变使这些个体容易出现认知症状，以及阿尔茨海默病（AD）病理在认知障碍中起什么作用。事实上，除了MB，其他神经影像学和实验室生物标志物似乎与血管asb积累有关。白质血管周围空间扩张（DPVS）（最近发现的脑血管疾病的重要标志）、蛛网膜下腔慢性出血（称为表面性铁沉着）和白质后侧高信号分布（慢性脑缺血的标志）都与晚期CAA有关。这可能与脑后区血管淀粉样蛋白沉积增加有关——有证据表明，CAA患者枕部匹兹堡化合物B （PiB）的相对负担升高，PET配体在体内检测纤维和血管淀粉样蛋白沉积。CAA患者也表现出脑脊液（CSF）中Aß40类淀粉样蛋白的耗竭。最后，病理上脑微梗死在CAA中很常见。目前的应用旨在研究a ß介导的血管病理在老年人认知症状中的作用。提出这一建议的关键问题是：1)是否存在一种神经影像学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引起的轻度认知症状患者不同的特殊神经心理特征？3)导致早期CAA患者认知能力下降的易感危险因素有哪些？

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?