THE ROLE OF ADVANCED CAA IN ALZHEIMER'S DEMENTIA

神经病理学和神经影像学证据表明，阿尔茨海默氏症和阿尔茨海默病之间存在大量重叠。 疾病（AD）和晚期脑血管（l-淀粉样蛋白（AB）沉积（脑淀粉样蛋白血管病，CAA）。 特别引人注目的是最近观察到的脑叶微出血（MB）CAA的标志性特征中 五分之一或更多的患者被诊断为AD。CAA是众所周知的血管脆性和破裂的原因， 导致出血性中风和心肌梗塞虽然更广泛地认识到其在出血性疾病中的作用， 中风、伴有髓鞘丢失的白色缺血证据和白色胶质增生灶已在 家族性和严重散发性CAA。最近，CAA严重程度和白色物质之间的联系 已经在AD大脑中发现了损伤。存在一个大型的AD患者亚组， 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。 这个问题被越来越多的证据放大，这些证据表明小血管疾病与AD协同作用。 病理导致更大的赤字比单独的过程。此外，最近的试验数据（ 在实验性Aft后死亡的受试者中， 疫苗接种）表明CAA可能是AD的抗淀粉样蛋白免疫疗法的副作用的基础。 由于AD相关MB的全部含义尚未确定，我们建议分析MB阳性和MB阴性。 AD阴性受试者，以确定AD加晚期CAA的认知特征。研究了两个交叉- 纵向分析和横向分析。我们将确定AD+晚期的神经影像学特征， CAA。研究了高分辨率MRI标记物对晚期CAA和AD的特异性。虽然严格 肺叶MB似乎对晚期CAA具有良好的特异性，它们充其量是一种间接标记物， 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 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（CSF）中AIMO的消耗和2）匹兹堡化合物B的相对枕骨负荷 （PiB）.初步数据证实了这些标记物在晚期CAA中的作用，但两者都没有被作为一种 在AD的背景下测量CAA。 相关性（参见说明）： 这些目标的成功实现不仅将揭示这一大型（和 迄今为止未研究的）AD患者亚组，而且也Vantage将来研究其 对免疫疗法的反应。将广泛使用与《公约》有关的资源， 马萨诸塞州阿尔茨海默病研究中心（MADRC）及其合作者，提供关键的 与MADRC临床和神经病理学核心和神经影像资源的协同作用，以及与 马萨诸塞州综合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.