Epidemiological and Genetic Investigations of Blood-Based Biomarkers for Alzheimer's Disease in the Multiethnic, Washington Heights, Inwood, Columbia Aging Project (WHICAP)

多民族、华盛顿高地、因伍德、哥伦比亚老龄化项目 (WHICAP) 中阿尔茨海默病血液生物标志物的流行病学和遗传学调查

• 批准号: 10407545
• 负责人: ADAM M BRICKMAN
• 金额: $ 266.29万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407545
• 关键词: Affect; African American; African American population; African Caribbean; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Biological; Biological Markers; Blood; Caribbean Hispanic; Cerebrospinal Fluid; Cerebrovascular Disorders; Classification; Classification Scheme; Clinical; Cognition; Cognitive; Communities; Community Networks; Cross-Sectional Studies; Cyclotrons; DNA; Data; Data Set; Dementia; Development; Diagnosis; Disease; Early Diagnosis; Education; Elderly; Environment; Epidemiology; Ethnic Origin; Ethnic group; Genetic; Genetic Predisposition to Disease; Genetic Research; Genotype; Goals; Image; Impaired cognition; Individual; Infarction; Investigation; Life Cycle Stages; Light; Magnetic Resonance Imaging; Measures; Mexican Americans; Mind; Molecular; Neighborhoods; Nerve Degeneration; Not Hispanic or Latino; Observational Study; Occupations; Outcome; Participant; Phenotype; Plasma; Population; Positron-Emission Tomography; Psychosocial Factor; Quantitative Trait Loci; Race; Risk Factors; SNP array; SNP genotyping; Sampling; Socioeconomic Status; Therapeutic Trials; Thick; Time; Universities; Variant; Vascular Diseases; Washington; White Matter Hyperintensity; Whole Blood; base; blood-based biomarker; brain magnetic resonance imaging; brain volume; cerebral atrophy; clinical diagnosis; cohort; endophenotype; epidemiology study; exome; follow-up; forest; genetic analysis; genome sequencing; genome-wide; health care availability; health disparity; imaging biomarker; improved; indexing; longitudinal analysis; magnetic resonance imaging biomarker; metabolic abnormality assessment; mild cognitive impairment; molecular imaging; multi-ethnic; neurofilament; neuroimaging marker; phenotypic data; polygenic risk score; prospective; protective factors; psychosocial; racial and ethnic; sex; social; social health determinants; tau Proteins; tau-1

ABSTRACT. The analysis of cerebrospinal fluid (CSF) and molecular PET biomarkers of Aβ and phospho-tau combined with MRI assessment of global and regional neurodegeneration led to the development of the “A/T/N” classification scheme for Alzheimer's disease (AD) that was intended to add precision to the diagnosis for clinical purposes, therapeutic trials and regulatory agencies. For observational epidemiological research the widespread use of these types of biomarkers is not possible because of the expense and limited access to cyclotrons necessary for molecular imaging and the difficulty in obtaining CSF in large studies. Further, it is clear that the relationship of biomarker values to clinical diagnoses can also differ by age, sex and race/ethnic group, and few studies have included diverse cohorts, representative of the population in the US. The advent of newly- established, blood-based biomarkers (Aβ40, Aβ42, p-tau217, neurofilament light chain or NFL) combined with brain MRI provides an opportunity to investigate the application of “A/T/N biomarker profile” in community-based, observational study, and create endophenotypes that can be used to identify genetic susceptibility. The Washington Heights, Inwood Columbia Aging Project (WHICAP) study is one of the few cohorts where the newly established blood-based biomarkers and well-established neuroimaging biomarkers for AD can be used to investigate a blood-based “A/T/N biomarker profile” across race/ethnic groups and by age and sex. Amyloid (plasma Aβ40 and Aβ42), Tau (plasma total tau and p-tau217), and Neurodegeneration (plasma neurofilament light [NfL], and MRI (brain volumes and cortical thickness) will be assessed in a longitudinal, multi-ethnic community-based elderly cohort (24% white non-Hispanic, 28% African American, 48% Caribbean Hispanic). The cohort has been genetically characterized, and has stored DNA, sera, and plasma. The effects of cerebrovascular disease “V” and psychosocial factors will also be investigated as potential modulators of the “A/T/N biomarker profile”. We will use publicly available genetic data in African American, Caribbean Hispanic and non-Hispanic white participants that included the WHICAP cohort to create ethnic-specific polygenic risk scores (ePRS). This will allow the identification of variants associated with the endophenotypes underlying the “A/T/N biomarker profile” and augment the ePRS association with the clinical diagnoses of AD. We will maintain longitudinal follow-up of the WHICAP cohort, adding participants only to account for attrition, collecting whole blood for plasma and sera, ascertaining psychosocial and biomedical risk and protective factors and obtaining structural MRI measures at least twice in participants over a four-year period. The overall goals of this project are to: 1) investigate variability in blood-based biomarkers and MRI measures in the “A/T/N biomarker profile” as it applies to clinical diagnoses in a multi-ethnic cohort; 2) investigate blood-based biomarkers as endophenotypes in genetic analyses for earlier detection and diagnosis of AD; 3) investigate how cerebrovascular disease and psychosocial factors modulate the use of blood-based and MRI biomarkers.

抽象的。A-β和磷酸化tau的脑脊液和分子PET生物标志物的分析 结合MRI对全局性和区域性神经退行性变的评估，导致A/T/N的发展 阿尔茨海默病(AD)的分类方案，旨在增加临床诊断的准确性 目的、治疗试验和监管机构。对于观察性流行病学研究，广泛的 使用这些类型的生物标记物是不可能的，因为回旋加速器的费用和使用机会有限 对于分子成像是必要的，在大型研究中获取脑脊液是困难的。此外，很明显， 生物标记物的价值与临床诊断的关系也可能因年龄、性别和种族/民族而不同，而且很少 研究包括了不同的人群，他们代表了美国的人口。新的-- 已建立的基于血液的生物标记物(Aβ40，Aβ42，p-tau217，神经丝轻链或NFL)与 脑MRI提供了一个机会，以调查“A/T/N生物标志物概况”在社区基础上的应用， 观察性研究，并创造可用于识别遗传易感性的内表型。 华盛顿高地因伍德哥伦比亚老龄化项目(WHICAP)的研究是少数几个队列研究之一 可以使用新建立的基于血液的生物标记物和成熟的神经成像生物标记物来诊断AD 研究基于血液的“A/T/N生物标记物概况”，跨越种族/民族以及年龄和性别。淀粉样蛋白 (血浆Aβ40和Aβ42)、Tau(血浆总tau和p-tau217)和神经变性(血浆神经丝 LIGH[NFL]和MRI(脑体积和皮质厚度)将在纵向、多种族进行评估 以社区为基础的老年人队列(24%非西班牙裔白人，28%非裔美国人，48%加勒比海拉美裔)。 这群人已经有了基因特征，并储存了DNA、血清和血浆。的影响 脑血管疾病“V”和心理社会因素也将作为潜在的调节因素进行调查。 “A/T/N生物标志物概况”。我们将在非裔美国人和加勒比拉美裔美国人中使用公开的基因数据 和非西班牙裔白人参与者，包括WHICAP队列，以产生种族特定的多基因风险 得分(EPR)。这将允许识别与潜在的内表型相关联的变体 “A/T/N生物标记物谱”，并增强EPRS与AD临床诊断的相关性。 我们将保持对WHICAP队列的纵向跟踪，增加参与者仅考虑自然减员， 采集血浆和血清的全血，确定心理社会和生物医学风险和保护因素 并在四年内对参与者进行至少两次结构磁共振测量。的总体目标 本项目的目的是：1)研究基于血液的生物标记物的变异性，以及在A/T/N生物标记物中的MRI测量方法 在多种族队列中应用于临床诊断；2)调查基于血液的生物标记物 遗传分析中的内表型用于AD的早期检测和诊断；3)调查 脑血管疾病和心理社会因素影响血液和核磁共振生物标记物的使用。