Cerebrovascular contributions to Alzheimer's disease in adults with Down Syndrome

项目总结 患有唐氏综合症(DS)的成年人在40岁之前就会出现阿尔茨海默病(AD)的病理，而且很多人 由于21号染色体的三倍体，在60岁之前出现痴呆症状，其中淀粉样蛋白 前体蛋白(APP)基因驻留。由于最近生活质量的提高和医学的进步， 患有DS的成年人的平均寿命正在增加，这使得高度依赖于年龄的AD和它的 认知和功能影响在这一人群中引发公共健康危机。尽管该领域的主要重点是 淀粉样蛋白、tau蛋白和神经退行性变(A/T/N)在AD中的致病级联，晚期有证据积累 发作性AD，AD的其他遗传形式，以及在我们在患有DS的成年人中的试点数据中，主要作用是 脑血管疾病在AD中的症状表现和可能的发病机制。这样做的目的是 这项研究旨在检查脑血管的神经成像、血液和神经病理标记物。 成人DS患者的功能障碍。在登记在阿尔茨海默氏症生物标记物联盟的550名患有DS的成年人中- 唐氏综合征(ABC-DS；U19 AG068054)我们将量化脑血管疾病的MRI标志物和 血管认知障碍的血浆生物标记物在基线和纵向访问中检查其 与年龄、普遍的认知诊断和5年期间的认知衰退有关。在尸检中 亚组(n~50)，我们将检测死后脑血管标记物，包括脑淀粉样血管病 (CAA)、微出血、神经炎症和神经血管单位的成分及其相关性 具有AD的病理和临床特点。这项工作符合美国国立卫生研究院的特殊利益通知(NOSI) Not-OD-20-025 for R01授予专注于DS并以编程方式与 了解唐氏综合症(INCLUDE)项目的终生共生状况调查。 我们的研究将通过了解DS中独特的血管轮廓来实现INCLUDE的目标，这将 为患有DS的成年人以及没有DS的人提供医学进展的信息，并通过连接现有的 资源(构成部分2)。这项拟议的研究将改变现有的关于脑血管作用的知识 DS和AD中的疾病，并指出治疗和预防策略。将测试以下目标。(1)至 检查脑血管疾病的MRI标记物与年龄、普遍认知诊断和事件的关系 成人DS患者5年间的认知诊断和认知衰退。(2)审查协会 血管认知障碍的血液生物标记物与年龄的关系，脑血管疾病的磁共振标记物， 以及流行的和偶发的诊断，以及认知能力下降，以及(3)尸检特征 脑血管神经病理学，与AD神经病理学的关系，下游后果，以及 来自传统尸检系列的成人DS的生前诊断及其与神经影像和临床的关系 预期的ABC-DS病例的结果。

PROJECT SUMMARY Adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology by 40 years of age, and many develop symptoms of dementia by 60 years of age due to the triplication of chromosome 21 where the amyloid precursor protein (APP) gene resides. Because of recent improvements in quality of life and medical advances, the average lifespan of adults with DS is increasing, making AD, which is strongly age dependent, and its cognitive and functional impacts a public health crisis in this population. Despite the field's primary focus on the amyloid, tau, and neurodegeneration (`A/T/N') pathogenic cascade in AD, there is evidence accumulating in late onset AD, other genetic forms of AD, and in our pilot data among adults with DS, of a primary role of cerebrovascular disease in AD symptom presentation and possibly disease pathogenesis. The purpose of this study is to examine neuroimaging, blood-based, and neuropathological markers of the cerebrovascular dysfunction in adults with DS. Among 550 adults with DS enrolled in the Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS; U19 AG068054) we will quantitate MRI markers of cerebrovascular disease and plasma biomarkers for vascular cognitive impairment at baseline and over longitudinal visits to examine their association with age, prevalent cognitive diagnosis, and cognitive decline over a 5-year period. In an autopsy subset (n~50), we will examine postmortem cerebrovascular markers, including cerebral amyloid angiopathy (CAA), microhemorrhages, neuroinflammation, and components of the neurovascular unit, and their association with AD pathology and clinical characteristics. The work is in line with NIH Notice of Special Interest (NOSI) NOT-OD-20-025 for R01 grant applications that focus on DS and that are programmatically aligned with the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project. Our study will meet the objectives of INCLUDE by understanding the unique vascular profile in DS, which will inform medical advances for adults with DS as well as for people without DS, and by connecting existing resources (Component 2). The proposed study will transform existing knowledge of the role of cerebrovascular disease in DS and AD and point to treatment and prevention strategies. The following aims will be tested. (1) To examine MRI markers of cerebrovascular disease with respect to age, prevalent cognitive diagnosis, and incident cognitive diagnosis and cognitive decline over a 5-year period in adults with DS. (2) To examine the associations of blood-based biomarkers for vascular cognitive impairment with age, MRI markers of cerebrovascular disease, and prevalent and incident diagnoses, and cognitive decline, and (3) To characterize postmortem cerebrovascular neuropathology, relationship to AD neuropathology, downstream consequences, and antemortem diagnosis in adults with DS from a legacy autopsy series and in relation to neuroimaging and clinical outcomes from prospective ABC-DS cases.