THE ROLE OF ADVANCED CAA IN ALZHEIMER'S DEMENTIA

神经病理学和神经成像证据表明，阿尔茨海默氏症之间有很大的重叠 疾病(AD)和晚期脑血管(L-淀粉样蛋白(AB))沉积(脑淀粉样血管病)。 尤其引人注目的是最近观察到的叶微出血(MB)，这是CAA的一个显著特征 诊断为阿尔茨海默病的患者中有五分之一或更多。CAA是众所周知的血管脆弱和破裂的原因， 导致出血性中风和MBS。尽管更广泛地认识到它在出血性疾病中的作用 中风，脑白质缺血伴髓鞘丢失和脑白质胶质细胞增生灶的证据已被注意到 家族性和严重的散发性CAA。最近，CAA严重程度与脑白质的关系 已发现阿尔茨海默病患者的大脑受损。晚期阿尔茨海默病患者中存在一大亚组 CAA提出了一个重要的问题，即血管淀粉样蛋白如何影响这些受试者的认知特征。 迅速增长的证据表明，小血管疾病与阿尔茨海默病的作用是一致的，这一问题被放大了 病理导致的赤字比任何一个单独的过程都要大。此外，最近的试验数据(发现 实验性AFT后死亡受试者脑内晚期CAA和血管周围炎症 疫苗接种)提示，CAA可能是抗淀粉样蛋白免疫疗法治疗AD的不良反应的基础。 由于AD相关MBS的完整含义仍未定义，我们建议分析MB-阳性和MB- 阴性AD受试者识别AD合并晚期CAA的认知特征。两者都在交叉学习- 并在横向和纵向上进行分析。我们将确定AD+高级患者的神经影像特征 CAA。使用针对晚期CAA和AD的高分辨率MRI标记物进行研究。尽管严格来说 叶状MBS对晚期CAA似乎具有良好的特异性，充其量是一种间接标记物，显示 晚期脑血管淀粉样蛋白的影响，而不是淀粉样蛋白本身。因此，第二个主要目标是 因此，目前的建议是通过最近确定的CAA的直接测量来分析AD患者：1) 脑脊液中Aimo的耗竭和2)匹兹堡化合物B的相对枕骨负荷 (PiB)。初步数据在晚期CAA中验证了这些标记，但这两个标记都没有作为 AD设置中的CAA测量。 相关性(请参阅说明}： 这些目标的成功完成不仅将有助于揭示这一大型(和 到目前为止还没有研究过的)AD患者亚组，但也为未来研究他们的 对免疫治疗的反应。将广泛使用与 马萨诸塞州阿尔茨海默病研究中心(MADRC)及其合作者，提供关键 与MADRC临床和神经病理核心和神经影像资源的协同作用，以及与 马萨诸塞州总医院中风研究中心的长期CAA研究项目。

Neuropathologic and neuroimaging evidence indicates that substantial overlap exists between Alzheimer's disease (AD) and advanced cerebrovascular (l-amyloid (AB) deposition (cerebral amyloid angiopathy, CAA). Particularly striking is the recent observation of lobar microbleeds (MB)a hallmark feature of CAAin a fifth or more of patients diagnosed with AD. CAA is a well-known cause of vessel fragility and rupture, leading to hemorrhagic strokes as well as MBs. Although more widely recognized for its role in hemorrhagic stroke, evidence of white matter ischemia with myelin loss and foci of white matter gliosis have been noted in both familial and severe sporadic CAA. Recently, associations between CAA severity and white matter damage have been identified in AD brains. The existence of a large subgroup of AD patients with advanced CAA raises the important question of how vascular amyloid impacts the cognitive profile of these subjects. This question is magnified by rapidly growing evidence that small vessel disease acts in concert with AD pathology to cause greater deficits than either process alone. Additionally, recent trial data (the finding of advanced CAA and perivascular inflammation in brains from subjects who died following experimental Aft vaccination) suggest that CAA may underlie adverse effects of anti-amyloid immunotherapies for AD. As the full meaning of AD-associated MBs is still undefined, we propose to analyze MB-positive and MB- negative AD subjects to identify the cognitive features of AD plus advanced CAA. studied both in cross- sectional and in a longitudinal analyses. We will identify the neuroimaging features of AD plus advanced CAA. studied with high-resolution MRI markers specific to both advanced CAA and AD. Although strictly lobar MBs appear to have good specificity for advanced CAA, they are at best an indirect marker, showing the effects of advanced cerebrovascular amyloid but not the amyloid itself. Thus, a second main goal of the current proposal is therefore to analyze AD patients by recently identified direct measures of CAA: 1) depletion of AIMO in cerebrospinal fluid (CSF) and 2) relative occipital burden of Pittsburgh Compound B (PiB). Preliminary data validates these markers in advanced CAA, but neither has been examined as a measure of CAA in the setting of AD. RELEVANCE (See instructions}: Successful completion of these aims will not only shed light on the natural history of this large (and heretofore unstudied) subgroup of AD patients, but also provide a vantage for future studies of their response to immunotherapy. There will be extensive use of the resources associated with the Massachusetts Alzheimer's Disease Research Center (MADRC) and its collaborators, providing key synergies with the MADRC clinical and neuropathological cores and neuroimaging resources, as well as with the long-standing CAA research program at the Massachusetts General Hospital Stroke Research Center.