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

项目总结/摘要 唐氏综合征（DS）患者患阿尔茨海默病（AD）的风险高于 普通民众。因此，他们被认为是抗AD治疗试验的理想目标人群; 然而，没有可靠措施来预测这一人群中痴呆症的发作。个体内认知 变异性（IICV），一个人在一个单一的神经心理学测试表现的变异性的量度。 时间点，是一种新的，低成本的，非侵入性的生物标志物的神经变性和早期痴呆的一般 人口然而，尚未在DS成人中研究IICV。因此，目前的提案将填补 通过描述成人中IICV、AD生物标志物和痴呆之间的关联， 在DS本提案的目标1和2使用来自阿尔茨海默氏生物标志物联盟-唐氏综合征的数据 （ABC-DS）研究，该研究目前由两个不同地点收集的认知和生物标志物数据组成。 时间点（基线和18个月），以计算记忆、执行功能和处理的IICV指标 速度，视觉空间结构和多域认知在300名成人DS。使用纵向ABC- 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- tau 217和NfL）和/或AD相关病理（Aβ-PET和tau-PET）（K99，Aim 1）。我们亦会研究 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， 基线时的IICV与痴呆的随访诊断以及认知功能下降相关， 基线到随访。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，跨文化的队列中测试目标1和2的结果指标， 来自华盛顿州和巴西圣保罗的成年DS患者，并包括与对照组的比较 一组患有常染色体显性AD的个体，由于其与早期纹状体淀粉样蛋白中的DS相似， β沉积（R 00，Aim 3）。为了实现这些目标，我们制定了一个全面的，有指导的培训 我计划（1）获得神经心理学，血浆生物标志物和 神经影像学;（2）拓宽我对常染色体显性AD之间的相似性和差异性的认识 （3）探讨AD风险的跨文化相似性和差异;（4）开发先进的 统计技能。在K99阶段获得的数据和培训将导致成功实施 高质量的国际研究项目，重点关注DS中的IICV和AD生物标志物。调查结果显示， 可能用于全球DS人群，增加早期干预和入选的机会 在抗AD试验中。K99的高强度培训和在各个领域具有广泛专业知识的导师的支持 该提案将为跨文化AD风险的独立科学事业提供基础 预测DS和其他高危人群。

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.