Optimizing PET spatial extent measures to detect the earliest amyloid-beta and tau accumulation and associated cognitive decline in preclinical Alzheimer's disease

优化 PET 空间范围测量以检测临床前阿尔茨海默病中最早的淀粉样蛋白 β 和 tau 积累以及相关的认知能力下降

• 批准号: 10721474
• 负责人: Michelle Elizabeth Farrell
• 金额: $ 12.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721474
• 关键词: Acceleration; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloidosis; Binding; Biological Markers; Biometry; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Communities; Complement; Computing Methodologies; Data; Dementia; Deposition; Detection; Disease; Disease Progression; Drug Kinetics; Early Diagnosis; Evaluation; Exhibits; Future; Growth; Heterogeneity; Impaired cognition; Individual; Inflammation; Intervention; Investigation; Learning; Maps; Measures; Mentors; Mentorship; Methods; Neocortex; Nerve Degeneration; Noise; Outcome; Participant; Pathogenesis; Pathologic; Physics; Pittsburgh Compound-B; Plasma; Positron-Emission Tomography; Predisposition; Prevention trial; Price; Primary Prevention; Process; Proliferating; Research; Risk; Role; Sampling; Sensitivity and Specificity; Statistical Data Interpretation; Stereotyping; Symptoms; Testing; Training; Translational Research; abeta accumulation; abeta deposition; aging brain; career; clinical translation; cognitive change; cognitive testing; digital; experience; follow-up; glial activation; improved; in vivo; longitudinal positron emission tomography; medical schools; multidisciplinary; neocortical; novel; pre-clinical; predictive marker; prevent; primary endpoint; programs; radiotracer; screening; secondary endpoint; simulation; statistics; synaptic function; tau Proteins; tau aggregation; translational potential; translational scientist; β-amyloid burden

Successful prevention of Alzheimer’s disease (AD) dementia may rely on intervention at the earliest possible point in the AD pathological cascade, hypothesized to be the accumulation of amyloid-beta (Aβ). The standard PET approach for Aβ detection is based on widespread cortical Aβ burden and often fails to capture early Aβ. The proposed K01 project will develop optimized spatial extent measures that allow for robust identification of individuals in an earlier stage of amyloidosis than previously studied. This approach should provide a more dynamic biomarker of A localization for investigating early A‘s role in the AD pathological cascade and has the potential to serve as a more sensitive outcome in future prevention trials. Aim 1 will use longitudinal data from clinically normal (CN) individuals from the Harvard Aging Brain Study (HABS) to 1) develop an optimized spatial extent metric based on a scientifically rigorous investigation of how different possible methods for computing spatial extent respond to simulated noise, 2) validate the sensitivity and specificity of the optimal spatial extent approach (EXT) to predict future A accumulation over 3-11 years, and 3) implement EXT in an independent sample of standard PET- screen fails from the AHEAD 3-45 Study to assess the alignment between plasma Aβ+ and EXT+ for detecting the earliest Aβ deposits. Aim 2 will use EXT to evaluate the earliest changes in tau using plasma biomarkers (ptau217) and flortaucipir-PET and assess whether EXT may provide a better predictive marker of those at risk for tau proliferation than standard cortical Aβ-PET approaches. Aim 3 will evaluate whether the improved quantification of the earliest A deposits with EXT allows for more sensitive detection of long-term and immediate cognitive changes associated with emerging A. These findings will help provide a framework for future prevention trials to intervene earlier in the disease process than has previously been attempted. Furthermore, the EXT approach will open a wide range of potential future directions to study how emerging Aβ relates to other important factors in AD pathogenesis (i.e. inflammation, synaptic function) to establish an independent research program. To help Dr. Michelle Farrell achieve these aims, a multidisciplinary mentorship team has been assembled from the Harvard Medical School community to complement didactic coursework in PET physics and pharmacokinetics, plasma biomarkers, advanced statistical analysis, and clinical trials. Dr. Reisa Sperling will serve as the primary mentor overseeing research and career progress and providing training in clinical trial design and conduct to maximize the translational potential of the planned research. Dr. Keith Johnson and Dr. Julie Price will serve as co-mentors to provide comprehensive training in PET research. The mentorship team will be rounded out by two research advisors (Dr. Rob Rissman: plasma biomarkers, Dr. Brian Healy: statistics) and two contributors (Dr. J. Alex Becker: PET simulations; Dr. Kathryn Papp: daily digital cognitive assessments). This comprehensive training plan will facilitate Dr. Farrell’s research and growth into an independent clinical translational scientist.

成功预防阿尔茨海默病 (AD) 痴呆症可能依赖于尽早干预 AD 病理级联中的一个点，假设是β-淀粉样蛋白 (Aβ) 的积累。标准 用于 Aβ 检测的 PET 方法基于广泛的皮质 Aβ 负荷，通常无法捕获早期 Aβ。 拟议的 K01 项目将开发优化的空间范围测量，以便稳健地识别 比以前研究的处于淀粉样变性早期阶段的个体。这种方法应该提供更多 A 定位的动态生物标志物，用于研究早期 A 在 AD 病理级联中的作用，并已 有可能在未来的预防试验中成为更敏感的结果。目标 1 将使用纵向数据 从哈佛大脑老化研究 (HABS) 中的临床正常 (CN) 个体到 1) 开发出一种优化的 空间范围度量基于对不同可能方法如何进行科学严格的调查 计算对模拟噪声的空间范围响应，2) 验证最佳方案的敏感性和特异性 空间范围方法 (EXT) 来预测未来 3-11 年的 A 积累，以及 3) 在 标准 PET 筛查的独立样本未能通过 AHEAD 3-45 研究评估对齐情况 血浆 Aβ+ 和 EXT+ 之间的关系，用于检测最早的 Aβ 沉积物。目标 2 将使用 EXT 来评估 使用血浆生物标志物 (ptau217) 和 flaucipir-PET 检测 tau 蛋白的最早变化，并评估 EXT 是否可能 与标准皮质 Aβ-PET 相比，为有 tau 增殖风险的人提供更好的预测标记 接近。目标 3 将评估是否可以通过 EXT 改进最早的 A 沉积物的量化 允许更灵敏地检测与新出现的相关的长期和即时认知变化 A。这些发现将有助于为未来的预防试验提供一个框架，以便在疾病早期进行干预 比以前尝试过的过程。此外，EXT 方法将开启广泛的 研究新兴 Aβ 与 AD 发病机制中其他重要因素的关系（即，未来的潜在方向） 炎症、突触功能）建立独立的研究计划。帮助米歇尔·法雷尔博士 为了实现这些目标，哈佛医学院组建了一支多学科指导团队 社区补充 PET 物理和药代动力学、血浆生物标志物、 高级统计分析和临床试验。 Reisa Sperling 博士将担任主要导师监督 研究和职业进步，并提供临床试验设计和实施方面的培训，以最大限度地提高 计划研究的转化潜力。 Keith Johnson 博士和 Julie Price 博士将担任联合导师 提供 PET 研究方面的全面培训。导师团队将由两项研究组成 顾问（Rob Rissman 博士：血浆生物标志物，Brian Healy 博士：统计）和两名贡献者（J. Alex 博士） Becker：PET 模拟； Kathryn Papp 博士：每日数字认知评估）。此次综合培训 该计划将促进法雷尔博士的研究并成长为一名独立的临床转化科学家。