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: 10536632
• 负责人: DAVID LOEWENSTEIN
• 金额: $ 68.93万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536632
• 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 region; Classification; Clinical Trials; Clinical Trials Design; Cognitive; Cognitive deficits; Dementia; Deposition; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Early identification; Elderly; Ethnic Origin; Exhibits; Failure; 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; System; 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 关注临床前阿尔茨海默病（AD）的新兴临床试验预计将是最重要的。 在疾病的早期甚至前驱阶段有效，在显著的多系统退化之前， 发生了。为此，新兴临床试验的成功关键在于能够识别和靶向 真正有AD风险的人。可靠地识别这些高危个体;然而，目前的成本 在大规模试验中是禁止的，因为依赖于AD生物标志物，如淀粉样蛋白成像， 对诊断的信心。为了促进临床前AD试验的可行性，该领域必须 制定临床结局指标，经验证可识别早期疾病状态， 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 最终优化临床试验入组。成果措施还必须有效地衡量潜力 治疗反应随时间的变化，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，MRI上AD易感区域的体积损失），并且考虑到 美国的西班牙裔人口不断增长。 我们的实验室一直处于发展评估范式的前沿， 并且特异于临床前AD。其中一个新的记忆范例，LASSI-L挖掘了从 主动语义干扰（frPSI），并已被证明是显着更敏感的早期认知 比学习效率低下或简单的遗忘率，如ADAS-Cog所测量的。LASSI-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， 在其他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 在患有遗忘型MCI（aMCI）和PreMCI的老年人中，易发区域表明这种范式代表了一种 早期AD的认知标志物我们现在已经大大扩展了我们早期的工作， 计算机化认知应激测试（CST），旨在更强烈地引出临床前AD的认知标志物。 在目前的研究中，我们打算通过以下方式验证这种新型且更强大的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）患者的表现， 与无认知障碍的老年人相比，与AD临床研究中采用的传统测量方法相比， 如ADAS-Cog等试验。我们还将研究科技委与生物学的相关性， AD的标志物：PET淀粉样蛋白负荷、体积和皮质厚度的MRI测量、DTI和tau负荷。 拟议的调查将提供一个无与伦比的机会，以验证和建立一个 专门设计用于检测临床前AD的新型且有前景的认知结果测量，用于 临床前AD试验作为潜在的筛选和结局指标。我们坚信， 为实地工作做出重要贡献。

项目成果

Associations Between Cognitive Functioning and Mortality in a Population-Based Sample of Older United States Adults: Differences by Sex and Education.

美国老年人群体样本中认知功能与死亡率之间的关联：性别和教育程度的差异。

• DOI: 10.1177/08982643221076690
• 发表时间: 2022
• 期刊: Journal of aging and health
• 影响因子: 2.8
• 作者: AdjoianMezzaca,Tamar;Dodds,LeahV;Rundek,Tatjana;ZekiAlHazzouri,Adina;Caunca,MichelleR;Gomes-Osman,Joyce;Loewenstein,DavidA;Schneiderman,Neil;Elfassy,Tali
• 通讯作者: Elfassy,Tali