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 患有唐氏综合征（DS）的成年人在40岁时发展成阿尔茨海默病（AD）病理，并且许多人 由于21号染色体的三倍化， 前体蛋白（APP）基因。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延长，这使得AD具有很强的年龄依赖性，并且其 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 淀粉样蛋白、tau蛋白和神经变性（“A/T/N”）致病级联，有证据表明， 在我们的DS成人试验数据中， 脑血管病在AD中的症状表现及可能的发病机制。这样做的目的 一项研究是检查脑血管的神经影像学、血液和神经病理学标志物， 成年DS患者的功能障碍。在阿尔茨海默氏症生物标志物联盟登记的550名患有DS的成年人中， 唐氏综合征（ABC-DS; U19 AG 068054），我们将定量脑血管疾病的MRI标志物， 基线和纵向访视时血管性认知障碍的血浆生物标志物，以检查其 与年龄、普遍认知诊断和5年内认知下降的相关性。在解剖 亚组（n~50），我们将检查死后脑血管标志物，包括脑淀粉样血管病 (CAA)微血管、神经炎症和神经血管单位的成分，以及它们之间的联系 AD的病理和临床特征。这项工作符合NIH特别关注通知（NOSI） NOT-OD-20-025，针对专注于DS并在程序上与 调查整个生命周期中的共现疾病，以了解唐氏综合征（INCLUDE）项目。 我们的研究将通过了解DS的独特血管特征来满足INCLUDE的目标， 为患有DS的成年人以及没有DS的人提供医学进展，并通过将现有的 资源（构成部分2）。这项拟议的研究将改变现有的知识，脑血管疾病的作用， 疾病在DS和AD和点的治疗和预防策略。以下目标将得到检验。(1)到 检查脑血管疾病的MRI标记物，包括年龄、普遍认知诊断和事件 认知诊断和认知功能下降超过5年的成年人与DS。(2)为了检查关联， 血管性认知障碍随年龄增长的血液生物标志物，脑血管疾病的MRI标志物， 和流行和事件的诊断，和认知能力下降，和（3）表征死后 脑血管神经病理学，与AD神经病理学的关系，下游后果，以及 来自遗留尸检系列的成年DS患者的死前诊断以及与神经影像学和临床 前瞻性ABC-DS病例的结局。