Intraindividual cognitive variability in aging adults with Down syndrome: associations with Alzheimer's disease plasma biomarkers, neuropathology and clinical dementia

患有唐氏综合症的老年人的个体内认知变异：与阿尔茨海默病血浆生物标志物、神经病理学和临床痴呆的关联

• 批准号: 10724057
• 负责人: Luciana Fonseca
• 金额: $ 12.76万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724057
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid deposition; Area; Biological Markers; Brazil; Cerebrospinal Fluid; Chronic Brain Damage; Clinical; Clinical Trials; Cognition; Cognitive; Cohort Studies; Collaborations; Control Groups; Corpus striatum structure; Data; Dementia; Deterioration; Diagnosis; Disease; Down Syndrome; Early Diagnosis; Early Intervention; Early identification; Ethnic Population; Family; Foundations; General Population; High Prevalence; Impaired cognition; Incidence; Individual; Intellectual functioning disability; International; Intervention; Knowledge; Linear Models; Link; Logistic Models; Longitudinal cohort; Longitudinal cohort study; Measures; Memory; Mentors; Modeling; Nerve Degeneration; Neurobiology; Neuropsychological Tests; Neuropsychology; Outcome Measure; Pathology; Pathway interactions; Peptides; Performance; Persons; Phase; Plasma; Population; Positron-Emission Tomography; Public Health; Quality of life; Research; Research Design; Resource-limited setting; Societies; Target Populations; Testing; Therapy trial; Time; Training; Universities; Visuospatial; Washington; Work; abeta deposition; autosomal dominant Alzheimer' s disease; career; cognitive function; cognitive performance; cohort; cost; dementia risk; design; executive function; follow-up; high risk; high risk population; improved; middle age; mild cognitive impairment; neuroimaging; neuropathology; novel; novel marker; performance tests; pre-clinical; processing speed; programs; recruit; research study; risk prediction; sex; skills; tau Proteins; translational applications; β-amyloid burden

PROJECT SUMMARY/ABSTRACT Individuals with Down syndrome (DS) are at higher risk for developing Alzheimer’s disease (AD) compared to the general population. As such, they are considered an ideal target population for anti-AD therapy trials; however, there is no reliable measure for predicting dementia onset in this population. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, is a novel, low-cost, non-invasive biomarker of neurodegeneration and early dementia for the general population. However, IICV has not been investigated in adults with DS. Therefore, the current proposal will fill this knowledge gap by characterizing the associations between IICV, AD biomarkers, and dementia in adults with DS. Aims 1 and 2 of this proposal use data from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study, which is currently composed of cognitive and biomarker data collected at two different timepoints (baseline and 18 months), to calculate IICV measures for memory, executive function and processing speed, visuospatial construction, and multidomain cognition in 300 adults with DS. Using the longitudinal ABC- DS data, we will first examine whether IICV is associated with AD plasma biomarkers (β-amyloid 42/40, p- tau217, and NfL) and/or AD-related pathology (Aβ-PET and tau-PET) (K99, Aim 1). We will also examine whether IICV is associated with the clinical presentation of dementia and cognitive decline (K99, Aim 2). We expect our analyses to show that IICV is positively associated with AD-related biomarkers and pathology, and that IICV at baseline is associated with a follow-up diagnosis of dementia as well as cognitive decline from baseline to follow-up. These data will be critical for optimizing the design of a new cohort study of adults with DS that will test the outcome measures from Aims 1 and 2 in a new, more diverse, cross-cultural cohort of adults with DS from Washington State and São Paulo, Brazil, and include comparisons with a control group of individuals with autosomal dominant AD, due to its similarity with DS in early striatal amyloid- β deposition (R00, Aim 3). To complete these aims, we have developed a comprehensive, mentored training plan for me to (1) gain expertise in the relationship between neuropsychology, plasma biomarkers and neuroimaging; (2) broaden my knowledge of the similarities and differences between autosomal dominant AD and AD in DS; (3) explore cross-cultural similarities and differences in AD risk; and (4) develop advanced statistical skills. The data and training obtained in the K99 phase will lead to the successful implementation of a high-quality, international research program focused on IICV and AD biomarkers in DS. Findings have great potential to be used with the DS population worldwide, increasing the chances of early interventions and inclusion in anti-AD trials. The intense training in the K99 and the support of mentors with extensive expertise in all areas of the proposal, will provide the foundation for an independent scientific career on cross-cultural AD risk prediction in DS and other high-risk populations.

项目概要/摘要 与正常人相比，唐氏综合症 (DS) 患者患阿尔茨海默病 (AD) 的风险更高 因此，他们被认为是抗 AD 治疗试验的理想目标人群； 然而，没有可靠的措施来预测这一人群痴呆症的发生。 变异性（IICV），衡量一个人在单一时间的神经心理学测试表现的变异性 timepoint，是一种新型、低成本、非侵入性的神经退行性变和早期痴呆生物标志物，适用于一般人群 然而，IICV 尚未在成人 DS 中进行研究，因此，目前的提案将填补这一空白。 通过描述 IICV、AD 生物标志物和成人痴呆症之间的关联来弥补这一知识差距 该提案的目标 1 和 2 使用来自阿尔茨海默病生物标志物联盟-唐氏综合症的数据。 （ABC-DS）研究，目前由在两个不同的地方收集的认知和生物标志物数据组成 时间点（基线和 18 个月），计算记忆、执行功能和处理的 IICV 测量 使用纵向 ABC- 方法对 300 名 DS 成人的速度、视觉空间构建和多域认知进行了研究。 DS 数据，我们将首先检查 IICV 是否与 AD 血浆生物标志物（β-淀粉样蛋白 42/40、p- tau217 和 NfL）和/或 AD 相关病理学（Aβ-PET 和 tau-PET）（K99，目标 1）。 IICV 是否与痴呆和认知能力下降的临床表现相关（K99，目标 2）。 我们希望我们的分析表明 IICV 与 AD 相关的生物标志物和病理学呈正相关， 基线 IICV 与痴呆症的后续诊断以及认知能力下降相关 这些数据对于优化 DS 成人新队列研究的设计至关重要。 这将在一个新的、更多样化的跨文化群体中测试目标 1 和 2 的结果衡量标准 来自华盛顿州和巴西圣保罗的患有 DS 的成年人，并包括与对照组的比较 常染色体显性 AD 个体组，由于其与早期纹状体淀粉样蛋白 DS 相似 β 沉积（R00，目标 3） 为了完成这些目标，我们开发了全面的指导培训。 我计划 (1) 获得神经心理学、血浆生物标志物和神经心理学之间关系的专业知识 神经影像学；（2）拓宽我对常染色体显性 AD 之间异同的认识 DS 中的 AD；(3) 探索 AD 风险的跨文化异同；(4) 开发高级知识； K99阶段获得的数据和培训将导致成功实施统计技能。 专注于 DS 中 IICV 和 AD 生物标志物的高质量国际研究项目取得了巨大的成果。 有可能在全球 DS 人群中使用，增加早期干预和包容的机会 在抗 AD 试验中，K99 的严格培训以及在各个领域拥有丰富专业知识的导师的支持。 该提案的内容将为跨文化 AD 风险的独立科学事业奠定基础 DS 和其他高危人群的预测。