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.

项目概要 预计重点关注临床前阿尔茨海默病 (AD) 的新兴临床试验将是最多的 在疾病的最早阶段甚至前驱阶段有效，在显着的多系统退化发生之前 发生。为此，新兴临床试验的成功至关重要的是能够识别和靶向 真正有 AD 风险的人。可靠地识别这些高危人群；然而，目前的成本 由于依赖淀粉样蛋白成像等 AD 生物标志物来增加 对诊断测定的信心。为了促进临床前 AD 试验的可行性，该领域必须 制定经过验证的临床结果衡量标准，以识别具有高水平的早期疾病状态 敏感性和特异性。反过来，这种方法将具有显着的成本效益，并且有潜力 最终优化临床试验入组。结果措施还必须有效衡量潜力 治疗反应随时间的变化与早期 AD 病理学的生物标志物（例如淀粉样蛋白负荷、 tau 沉积、MRI 上 AD 易发区域的体积损失），并且可以跨文化应用 美国拉美裔人口不断增长。 我们的实验室一直处于开发敏感评估范式的前沿 并针对临床前 AD。 LASSI-L 就是这样一种新颖的记忆范式，它利用失败来恢复 主动语义干扰（frPSI），并已被证明对早期认知更加敏感 缺陷比学习效率低下或简单的遗忘率（由 ADAS-Cog 测量）更高。拉西-L 在检测临床前 AD 方面也优于其他广泛使用的措施。更具体地说，frPSI 有 在其他认知正常但淀粉样蛋白含量高且 AD 患者体积减少的老年人中观察到 患有遗忘性 MCI (aMCI) 和 PreMCI 的老年人中的易发区域表明，这种范式代表了 AD 早期的认知标志。我们现在已经显着扩展了我们早期的工作，以开发 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。 在当前的研究中，我们打算验证这种新颖且更强大的 CST 在临床前 AD 试验中的使用 检查 240 名患有早期 MCI (eMCI) 的西班牙裔和非西班牙裔个体的表现 与无认知障碍的老年人相比以及与 AD 临床中采用的传统措施相关 纵向试验，例如 ADAS-Cog。我们还将研究 CST 与生物的相关性 AD 标志物：PET 淀粉样蛋白负荷、MRI 体积和皮质厚度测量、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 新颖且有前景的认知结果测量，专门用于检测临床前 AD，用于 临床前 AD 试验作为潜在的筛查和结果测量。我们坚信这可以 为该领域做出重要贡献。

项目成果

Persistent Failure to Recover from Proactive Semantic Interference on the Cognitive Stress Test Differentiates Between Amnestic Mild Cognitive Impairment, Pre-Mild Cognitive Impairment, and Cognitively Unimpaired Older Adults.

认知压力测试中持续未能从主动语义干扰中恢复可以区分遗忘性轻度认知障碍、轻度认知障碍前期和认知未障碍的老年人。

• 发表时间: 2022
• 作者: Loewenstein, David A;Curiel Cid, Rosie E;Kitaigorodsky, Marcela;Ortega, Alexandra;Hincapie, Diana;Zheng, D Diane;Amaya, Alexandra;Gallardo, Liz;Manso, Leslie;Sosa, Jaylene;Crocco, Elizabeth A
• 通讯作者: Crocco, Elizabeth A

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。

• 发表时间: 2022-10
• 影响因子: 2.8
• 作者: Adjoian Mezzaca, Tamar;Dodds, Leah V;Rundek, Tatjana;Zeki Al Hazzouri, Adina;Caunca, Michelle R;Gomes;Loewenstein, David A;Schneiderman, Neil;Elfassy, Tali
• 通讯作者: Elfassy, Tali

Clinical Heart Failure Among Patients With and Without Severe Mental Illness and the Association With Long-Term Outcomes.

患有和不患有严重精神疾病的患者的临床心力衰竭及其与长期结果的关联。

• 发表时间: 2021
• 作者: Polcwiartek, Christoffer;Loewenstein, Daniel;Friedman, Daniel J;Johansson, Karin G;Graff, Claus;Sørensen, Peter L;Nielsen, René E;Kragholm, Kristian;Torp;Søgaard, Peter;Jensen, Svend E;Jackson, Kevin P;Atwater, Brett D
• 通讯作者: Atwater, Brett D