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

患有唐氏综合症的成人中脑血管对阿尔茨海默病的影响

• 批准号: 10539086
• 负责人: ADAM M BRICKMAN
• 金额: $ 307.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539086
• 关键词: Address; Adult; Age; Age-Years; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein Precursor; Angiogenic Proteins; Applications Grants; Astrocytes; Atherosclerosis; Autopsy; Biological Markers; Biostatistics Core; Blood; Blood Vessels; Categories; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular Trauma; Characteristics; Chromosome 21; Clinical; Cognitive; Cohort Studies; Data; Dementia; Diagnosis; Diagnostic; Disease; Down Syndrome; Elderly; Endothelial Cells; Endothelium; Enrollment; Frequencies; Functional disorder; Gender; Gene Proteins; Genetic Risk; Genotype; Head; Impaired cognition; Individual; Infarction; Inflammatory; Infrastructure; Intervention; Investigation; Knowledge; Late Onset Alzheimer Disease; Literature; Longevity; Magnetic Resonance Imaging; Medical; Nerve Degeneration; Other Genetics; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pericytes; Persons; Plasma; Population; Positioning Attribute; Prevention strategy; Proteins; Public Health; Quality of life; Resources; Risk; Role; Series; Severities; Signal Transduction; Symptoms; Testing; United States National Institutes of Health; Vascular Cognitive Impairment; Visit; White Matter Hyperintensity; Work; age related; base; blood-based biomarker; cerebral microbleeds; cerebrovascular; cerebrovascular health; cerebrovascular lesion; clinical diagnosis; cohort; comorbidity; data resource; in vivo; interest; lens; mild cognitive impairment; neuroimaging; neuroimaging marker; neuroinflammation; neuropathology; neurovascular unit; prospective; sex; tau Proteins; treatment strategy; virtual

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.

项目摘要 唐氏综合症（DS）的成年人在40岁时发展出阿尔茨海默氏病（AD）病理学，许多年龄 由于淀粉样蛋白的三染色体的一式字母，在60岁时出现痴呆症的症状 前体蛋白（APP）基因住宅。由于最近的生活质量和医疗进步的改善， DS成年人的平均寿命正在增加，制作AD，这是强烈依赖年龄的，并且它 认知和功能影响这一人群的公共卫生危机。尽管该领域的主要重点是 AD中的淀粉样蛋白，TAU和神经变性（“ A/T/N）的致病性级联 发病AD，其他AD的其他遗传形式以及DS成年人的试验数据中， AD症状表现和可能的疾病发病机理中的脑血管疾病。这个目的 研究是为了检查脑血管的神经影像学，基于血液和神经病理学标志物 DS成人的功能障碍。在550名患有DS的成年人中，在阿尔茨海默氏症的生物标志物联盟中 唐氏综合症（ABC-DS; U19 AG068054）我们将量化脑血管疾病的MRI标记和 基线和纵向访问时血管认知障碍的血浆生物标志物以检查其 与年龄，普遍的认知诊断和认知能力下降相关联。在尸检中 子集（n〜50），我们将检查术后脑血管标记，包括脑淀粉样血管病 （CAA），微生物检查，神经炎症和神经血管单元的组成部分及其关联 具有AD病理和临床特征。这项工作符合NIH的特殊兴趣通知（NOSI） R01赠款应用程序的NOT-OD-20-025，该应用程序专注于DS，并且与该应用程序在编程中与 研究整个生命周期的同时发生条件，以了解唐氏综合症（包括）项目。 我们的研究将通过了解DS中的独特血管轮廓来满足包括的目标 告知DS成年人以及无DS的人的医疗进展，并通过连接现有 资源（组件2）。拟议的研究将改变有关脑血管作用的现有知识 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）到 检查脑血管疾病的MRI标记，相对于年龄，普遍的认知诊断和事件 DS成年人在5年内的认知诊断和认知能力下降。 （2）检查关联 伴有血管认知障碍的血液生物标志物，年龄，脑血管疾病的MRI标记， 并且普遍存在和事件诊断，认知能力下降，以及（3）表征验尸 脑血管神经病理学，与AD神经病理学的关系，下游后果和 来自传统尸检系列的DS的成年人的Anemontem诊断，与神经影像学和临床有关 预期ABC-DS案件的结果。