A Novel Computerized Cognitive Stress Test Designed for Clinical Trials in Early Alzheimer's: Relationship with Multimodal Imaging Biomarkers in Diverse Cultural Groups

专为早期阿尔茨海默病临床试验设计的新型计算机认知压力测试：与不同文化群体中多模态成像生物标志物的关系

• 批准号: 10322102
• 负责人: DAVID LOEWENSTEIN
• 金额: $ 71.77万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322102
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Assessment tool; Atrophic; Biological Markers; Brain; Clinical Trials; Clinical Trials Design; Cognitive; Cognitive deficits; Dementia; Deposition; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Elderly; Exhibits; Failure; Gold; Hispanic; Hispanic Populations; Impaired cognition; Individual; Investigation; Laboratories; Learning; Magnetic Resonance Imaging; Measurement; Measures; Memory; Multimodal Imaging; Neuropsychology; Not Hispanic or Latino; Outcome Measure; Participant; Performance; Positron-Emission Tomography; Process; Risk; Semantics; Sensitivity and Specificity; Stress Tests; Testing; Thick; Time; United States; Work; amnestic mild cognitive impairment; amyloid imaging; brain volume; clinical outcome measures; clinical trial enrollment; cognitive change; cohort; computerized; cost; cost effective; design; early detection biomarkers; forgetting; high risk; imaging biomarker; indexing; instrument; mild cognitive impairment; multimodal neuroimaging; neuroimaging marker; novel; pre-clinical; regional atrophy; screening; success; tau Proteins; treatment response

Project Summary Emerging clinical trials focusing on preclinical Alzheimer's disease (AD) are expected to be most effective in the earliest or even prodromal stages of illness, before significant multi-system degeneration has occurred. To that end, it is critical to the success of emerging clinical trials to be able to identify and target individuals that are truly at-risk for AD. Reliably identifying these at-risk individuals; however, is currently cost prohibitive in large-scale trials given the reliance on AD biomarkers such as amyloid imaging to increase confidence in the diagnostic determination. To facilitate the feasibility of preclinical AD trials, the field must develop clinical outcome measures that are validated to identify early disease states with high levels of sensitivity and specificity. This approach in turn, would be significantly cost effective and has the potential to ultimately optimize clinical trial enrollment. Outcome measures must also be effective in measuring potential changes in treatment response over time, be related to biomarkers of early AD pathology (e.g., amyloid load, tau deposition, volumetric loss in AD prone regions on MRI), and be cross-culturally applicable given the growing Hispanic population in the United States. Our laboratory has been at the forefront of developing assessment paradigms that are both sensitive and specific to preclinical AD. One such novel memory paradigm, the LASSI-L taps the failure to recover from proactive semantic interference (frPSI) and has been shown to be significantly more sensitive to early cognitive deficits than learning inefficiency or simple rate of forgetting as is measured by the ADAS-Cog. The LASSI-L has also outperformed other widely used measures in detecting preclinical AD. More specifically, frPSI has been observed in otherwise cognitively normal elders with high amyloid load and decreased volumes in AD prone regions among elders with amnestic MCI (aMCI) and PreMCI suggesting that this paradigm represents a cognitive marker of very early AD. We have now significantly expanded our earlier work to develop a computerized Cognitive Stress Test (CST), designed to more strongly elicit cognitive markers of preclinical AD. In the current study, we intend to validate this novel and more powerful CST for use in preclinical AD trials by examining the performance of 240 Hispanic and non-Hispanic individuals with early stage MCI (eMCI) as compared to elders with no cognitive impairment and in relation to traditional measures employed in AD clinical trials such as the ADAS-Cog, longitudinally. We will also examine the relatedness of the CST to biological markers of AD: PET amyloid load, MRI measures of volume and cortical thickness, DTI and tau burden. The proposed investigation will provide an unparalleled opportunity to validate and establish a novel and promising cognitive outcome measure specifically designed to detect preclinical AD, for use in preclinical AD trials as both potential screening and outcome measures. We strongly believe that this can result in critical contributions to the field.

项目摘要 新出现的针对临床前阿尔茨海默病(AD)的临床试验预计将是 在疾病的最早阶段甚至是前驱阶段有效，在显著的多系统退化之前 发生了。为此，能够识别和确定目标是新兴临床试验成功的关键 真正有患AD风险的人。可靠地识别这些高危个人；然而，目前的成本 在大规模试验中令人望而却步，因为依赖于AD生物标记物，如淀粉样蛋白成像 对诊断决心的信心。为了促进临床前AD试验的可行性，该领域必须 开发经过验证的临床结果衡量标准，以识别早期疾病状态，这些疾病的水平高 敏感性和特异性。反过来，这种方法将具有显著的成本效益，并有可能 最终优化临床试验招生。结果衡量标准还必须有效地衡量潜力。 随着时间的推移，治疗反应的变化与早期AD病理的生物标志物(例如，淀粉样蛋白负荷， Tau沉积，MRI上易患AD区域的体积损失)，并可跨文化适用，因为 美国不断增长的拉美裔人口。 我们的实验室一直处于开发既敏感又敏感的评估范例的前沿 并且对临床前AD具有特异性。就是这样一种新的记忆范式，Lassi-L敲击了失败的恢复 前瞻语义干扰(FrPSI)，已被证明对早期认知更敏感 缺陷比学习效率低下或简单的健忘率，由ADAS-COG衡量。拉丝--L 在检测临床前AD方面也优于其他广泛使用的方法。更具体地说，frPSI具有 在认知正常的老年人中观察到高淀粉样蛋白负荷和AD体积减少 遗忘性MCI(AMCI)和PreMCI的老年人易发区域提示这一范式代表着 AD早期的认知标记物。我们现在已经大大扩展了我们早期的工作，以开发一种 计算机化认知压力测试(CST)，旨在更强烈地引发临床前AD的认知标记。 在目前的研究中，我们打算通过以下方式验证这种新颖且更强大的CST用于临床前AD试验 检查240名西班牙裔和非西班牙裔早期MCI(EMCI)AS患者的表现 与无认知障碍的老年人相比，以及与AD临床使用的传统测量方法的关系 纵向试验，如ADAS-Cog。我们还将研究CST与生物学的关系 AD的标志物：PET淀粉样蛋白负荷，MRI测量体积和皮质厚度，DTI和tau负荷。 拟议的调查将提供一个无与伦比的机会来验证和建立 专为检测临床前AD而设计的新颖且前景看好的认知结果测量方法，用于 临床前AD试验作为潜在的筛查和结果衡量标准。我们坚信，这可以 对这一领域作出了重大贡献。