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

项目摘要/摘要 唐氏综合征(DS)患者患阿尔茨海默病(AD)的风险比 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，没有可靠的方法来预测这一人群中痴呆症的发病。个体内认知 变异性(IICV)，衡量一个人在一次测试中的神经心理测试表现的变异性 Timepoint是一种新的、低成本的、非侵入性的神经退行性变和早期痴呆的生物标志物 人口。然而，IICV尚未在患有DS的成人中进行研究。因此，目前的提案将填补 通过表征IICV、AD生物标记物和成人痴呆之间的联系，这一知识差距 使用DS。该提案的目标1和目标2使用了阿尔茨海默病生物标记物协会唐氏综合症的数据 (ABC-DS)研究，该研究目前由在两个不同的 时间点(基线和18个月)，以计算记忆、执行功能和处理的IICV测量 300例成人DS患者的速度、视觉空间构建和多领域认知。使用纵向ABC- DS数据，我们将首先检查IICV是否与AD血浆生物标记物(β-淀粉样蛋白42/40，p- Tau217和NFL)和/或AD相关病理(Aβ-PET和tau-PET)(K99，目标1)。我们还将检查 IICV是否与痴呆症和认知功能下降的临床表现有关(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， 而基线时的IICV与痴呆症的后续诊断以及 后续行动的基线。这些数据将是优化成人DS队列研究设计的关键 这将考验目标1和目标2在一个新的、更多样化的、跨文化的 来自华盛顿州和巴西S的成年DS患者，并与对照组进行比较 常染色体显性阿尔茨海默病的个体群体，由于其与纹状体淀粉样蛋白早期的DS相似。 β沉积(R00，目标3)。为了实现这些目标，我们制定了一项全面的、有指导的培训 我计划(1)获得神经心理学、血浆生物标记物和 神经成像；(2)拓宽了我对常染色体显性阿尔茨海默病的异同的认识 (3)探讨跨文化在AD风险方面的异同；(4)发展高级 统计技能。在K99阶段获得的数据和培训将导致成功实施 高质量的国际研究计划集中在DS的IICV和AD生物标志物上。研究结果有很大的意义 有可能用于世界各地的DS人群，增加早期干预和纳入的机会 在抗AD试验中。在K99赛道上的密集培训和在所有领域拥有广泛专业知识的导师的支持 将为独立研究跨文化AD风险的科学事业奠定基础 在DS和其他高危人群中进行预测。

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.