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

成功预防阿尔茨海默病(AD)痴呆症可能依赖于尽可能早的干预 阿尔茨海默病病理级联中的一个点，推测是淀粉样β蛋白(Aβ)的堆积。标准 用于检测Aβ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，以允许稳健地识别 比以前研究的更早的淀粉样变性的个体。这种方法应该提供更多 A定位动态生物标记物研究早期S在AD病理性级联反应中的作用 在未来的预防试验中有可能成为更敏感的结果。目标1将使用纵向数据 从哈佛衰老脑研究(HABS)的临床正常(CN)个体到1)发展出优化的 空间范围度量基于对不同可能的方法如何进行科学严格的调查 计算空间范围对模拟噪声的响应；2)验证优化算法的灵敏度和特异度 空间扩展方法(EXT)用于预测未来3-11年的积累；3)在 标准PET-Screen的独立样本不能评估前面3-45项研究的对准情况 在血浆Aβ和EXT之间检测最早的Aβ沉积。目标2将使用EXT来评估 使用血浆生物标记物(Ptau217)和flortaucipir-PET检测tau的最早变化，并评估EXT是否可能 比标准皮质Aβ-PET能更好地预测那些有tau增殖风险的人 接近了。目标3将评估对最早的具有EXT的A矿床的改进量化 允许更灵敏地检测与新出现的 一辆。这些发现将有助于为未来的预防试验提供一个框架，以便更早地对疾病进行干预 进程比以前尝试的更多。此外，EXT方法将开启广泛的 未来可能的方向是研究新出现的Aβ如何与AD发病机制中的其他重要因素(即 炎症、突触功能)建立一个独立的研究计划。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个多学科指导团队 社区以补充PET物理和药物动力学、血浆生物标记物、 先进的统计分析和临床试验。Reisa Sperling博士将作为主要导师监督 研究和职业发展，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 计划研究的翻译潜力。基思·约翰逊博士和朱莉·普莱斯博士将担任共同导师 提供PET研究方面的全面培训。导师团队将通过两项研究来完善 顾问(Rob Rissman博士：血浆生物标记物，Brian Healy博士：统计学)和两位贡献者(J.Alex博士 Becker：宠物模拟；Kathryn Papp博士：每日数字认知评估)。这次综合培训 该计划将促进法雷尔博士的研究和成长为一名独立的临床翻译科学家。

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.