Detection of early cognitive change: Linking to clinically meaningful outcomes (Project 4)

检测早期认知变化：与具有临床意义的结果相关（项目 4）

• 批准号: 10541814
• 负责人: REISA A. SPERLING
• 金额: $ 27.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541814
• 关键词: Acceleration; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anxiety; Artificial Intelligence; Behavior; Behavioral; Blood Vessels; Brain; Clinical; Clinical Trials; Cognitive; Cognitive aging; Computer software; Data; Disease Marker; Early Diagnosis; Executive Dysfunction; Exposure to; Face; Failure; Future; Genetic; Goals; Heterogeneity; Home; Image; Impaired cognition; Impairment; Individual; Learning; Life; Life Experience; Link; Loneliness; Measures; Mental Depression; Modality; Modeling; Multimodal Imaging; Names; Neocortex; Nerve Degeneration; Neuropsychology; Outcome; Participant; Pathology; Patient Self-Report; Pattern; Performance; Phase; Positron-Emission Tomography; Prevention trial; Process; Reaction Time; Reporting; Risk; Series; Signal Transduction; Specificity; Testing; Time; Woman; Work; abeta accumulation; aging brain; apolipoprotein E-4; clinically relevant; cognitive change; cognitive function; cognitive process; cognitive testing; cohort; digital; digital technology; follow-up; formycin triphosphate; functional decline; improved; indexing; memory retention; mild cognitive impairment; molecular pathology; neocortical; neurobehavioral; novel; paired stimuli; pre-clinical; prevent; protective factors; resilience; sex; social engagement; tau Proteins; tau aggregation

SUMMARY—PROJECT 4: COGNITION. Given the series of disappointing clinical trial results at symptomatic stages of Alzheimer’s disease (AD), it has become even more urgent to elucidate the temporal relationships between accumulation of the molecular pathology of AD and the emergence of the earliest clinical manifestations. Over the second cycle of Project 4, we found consistent evidence that elevated amyloid-beta (aβ) is associated with future cognitive decline; however, there is considerable heterogeneity in rates of decline. It is increasingly clear that aβ in isolation is not sufficient for imminent decline, and it is possible that aβ becomes much less relevant once tau pathology and neurodegeneration are widespread. Thus, we now seek to better understand the patterns of cognitive change associated with the earliest phases of accumulation of both aβ and tau, even below current thresholds for abnormality, and to characterize the “pre-preclinical” phase of AD, as well as the factors that promote successful aging and resilience to cognitive decline. At the other end of the preclinical AD spectrum, we will investigate whether early cognitive change is predictive of progression to clinical impairment, as we will have up to 15 years of follow-up. In Aim 1, we strive to further elucidate the temporal association between longitudinal aβ and tau accumulation and cognitive trajectories. In addition to our work with the Preclinical Alzheimer Cognitive Composite (PACC), we will go deeper and focus on the specific cognitive processes associated with the earliest accumulation of aβ and tau, in the context of the multiple factors that may interact with these pathologies. In Aim 2, we will utilize digital technology to advance our work to go faster by detecting cognitive change more rapidly and with greater specificity and accuracy. Our initial work using home iPAD testing revealed a marked lack of “practice effect” despite repeated exposure to face-name pair stimuli every month on the iPad, associated with elevated aβ. We now propose to test whether we can detect a similar pattern of diminished practice effect over a period of days. We have also begun working with an Artificial Intelligence (AI) software platform using a digital pen to capture subtle cognitive inefficiencies in non-memory processes. In Aim 3, we will go broader, beyond cognitive testing, to examine clinically relevant measures that include self- and study-partner report of cognitive function, every day activities, and neurobehavioral alterations to elucidate potential bi-directional relationships and temporal sequence of these changes along the trajectory of preclinical AD. We will use these measures to assess the “clinical meaningfulness” of early cognitive change, and to improve our predictions of progression to clinical impairment, in combination with imaging AD markers. Project 4 will leverage the rich longitudinal neuropsychological, behavioral, and multi-modality imaging data available on the HABS cohort to improve our understanding of relationships between the accumulation of aβ and tau in the aging brain and cognitive trajectories, and ultimately to inform ongoing and future trials aiming to prevent cognitive decline.

摘要 - 项目4：认知。考虑到症状的一系列令人失望的临床试验结果 阿尔茨海默氏病（AD）的阶段，阐明临时关系变得更加紧迫 在AD分子病理学的积累与最早的临床出现之间 表现。在项目4的第二个周期中，我们发现了一致的证据表明淀粉样蛋白β升高 （Aβ）与未来的认知下降有关；但是，比率有很大的异质性 衰退。越来越明显的是，孤立的Aβ不足以使即将下降，并且Aβ有可能 一旦Tau病理学和神经退行性广泛，就变得不那么重要了。那我们现在正在寻找 更好地了解与最早积累相关的认知变化模式 Aβ和TAU，甚至低于当前阈值以确保绝对性，并表征“预典型”阶段 AD的以及促进对认知能力下降的成功衰老和韧性的因素。在另一端 在临床前广告光谱中，我们将研究早期认知变化是否可以预测进展 临床障碍，因为我们将进行长达15年的随访。在AIM 1中，我们努力进一步阐明 纵向Aβ与TAU积累与认知轨迹之间的临时关联。此外 我们与临床前阿尔茨海默氏症认知复合材料（PACC）的合作，我们将更深入地关注 在与Aβ和TAU最早积累相关的特定认知过程中 可能与这些病理相互作用的多种因素。在AIM 2中，我们将利用数字技术来推进 我们的工作以更快地检测认知变化，并具有更大的特异性和准确性来更快。 我们使用家用iPad测试的最初工作表明，尽管有反复的暴露 每月在iPad上面对面名的刺激，与Aβ升高有关。我们现在建议测试 我们是否可以在几天内检测出类似的实践效果模式。我们也有 开始使用数字笔与人工智能（AI）软件平台一起工作以捕获微妙的 在非记忆过程中的认知效率低下。在AIM 3中，我们将更广泛，超越认知测试， 每天都包括自我和研究合作者报告，包括自我和研究合作者报告，每天 活动和神经行为改变，以阐明潜在的双向关系和临时性 这些变化沿临床前AD轨迹的序列。我们将使用这些措施评估 早期认知变化的“临床意义”，并改善我们对临床发展的预测 损害，结合成像广告标记。项目4将利用丰富的纵向 HABS队列上可用的神经心理学，行为和多模式成像数据可改善我们的 了解Aβ和TAU在衰老大脑中的积累与认知之间的关系 轨迹，并最终告知正在进行的和将来的试验旨在防止认知能力下降。