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 重点关注临床前阿尔茨海默氏病（AD）的新兴临床试验预计最多 在最早甚至疾病的前驱阶段有效，在重大多系统变性之前 发生。为此，对于能够识别和靶向的新兴临床试验的成功至关重要 真正对广告的人。可靠地识别这些处于危险的人；但是，目前费用 鉴于依赖于AD生物标志物（例如淀粉样蛋白成像）增加的大规模试验中的过度试验 对诊断确定的信心。为了促进临床前广告试验的可行性，该领域必须 制定临床结果指标，以识别具有高水平的早期疾病状态 灵敏度和特异性。反过来，这种方法将具有显着的成本效益，并且有可能 最终优化临床试验入学率。结果指标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病理学的生物标志物有关（例如，淀粉样蛋白负荷， tau沉积，在MRI上易于AD区域的体积损失），并在跨文化上适用 在美国增加西班牙裔人口。 我们的实验室一直处于开发既敏感的评估范例的最前沿 并针对临床前广告。一个这样的新颖记忆范式，lassi-l敲击未能从 主动语义干扰（FRPSI），已被证明对早期认知更为敏感 与学习效率低下或简单的遗忘速度相比，ADAS-COG衡量的障碍。 lassi-l 在检测临床前AD方面，还超过了其他广泛使用的措施。更具体地说，frpsi有 在否则具有高淀粉样蛋白负荷和AD体积减少的认知正常长老中观察到 俯卧的长老MCI（AMCI）和PERMCI的地区俯卧，这表明该范式代表了一个 非常早期的认知标记。现在，我们已经大大扩展了我们早期的工作，以开发 计算机认知应力测试（CST），旨在更强烈地引起临床前AD的认知标记。 在当前的研究中，我们打算通过通过 将240名西班牙裔和非西班牙裔人的表现与早期MCI（EMCI）的表现为 与没有认知障碍的长者相比，与广告临床中采用的传统措施有关 纵向的试验，例如ADAS-COG。我们还将检查CST与生物学的相关性 AD的标记：PET淀粉样蛋白负载，体积和皮质厚度的MRI度量，DTI和Tau负担。 拟议的调查将为验证和建立一个无与伦比的机会 专门设计用于检测临床前AD的新颖和有希望的认知结果度量，用于用于 临床前广告试验既是潜在的筛查和结果措施。我们坚信这可以 导致对该领域的关键贡献。