The impact of early medial temporal lobe Tau in human cognitive aging

项目总结 阿尔茨海默病(AD)痴呆是一种进行性神经退行性疾病，在老年人中很常见 个体，通常与间歇性记忆丧失有关。阿尔茨海默病的病理生理过程开始 在痴呆症临床症状出现前几十年，提供了一个及早了解的机会 疾病机制和这种病理在“正常”衰老中对记忆衰退的贡献。沿着这些 在整个寿命中，临床正常范围内的记忆力下降都可以观察到，表现出微妙的 但在20岁的S和80岁的S之间，每十年都会持续减少。有趣的是，这两个标志 阿尔茨海默病的病理机制是，牛磺酸积聚到神经纤维缠结(NFT)和β-淀粉样蛋白(Aβ)积聚到 斑块，显示明显的时间进程和整个生命周期的区域参与。具体地说，NFTs受到限制 中年常见，老年人普遍存在(50%的50岁和90%的人 70岁的人中有β)，而A NFT异常在中年并不常见，但 多见于老年人，且倾向于分布于整个皮质(60岁时为10%，75岁时为30% 老的)。内嗅皮层和内侧颞叶(MTL)其他部分的NFTs加重 新皮质与β积聚结合在一起。人类PET成像的最新进展使活体成像成为可能 Tau积累的可视化，为确定Tau积累的影响提供了关键机会 牛磺酸和A-β在记忆衰退中的协同作用。然而，能够 使用第一代Tau示踪剂，如AV1451，直接从海马区测量PET信号 被邻近海马区的脉络丛的非靶点结合所损害。最近发展起来的 显示与脉络丛非靶向结合较少的第二代示踪剂，如[18]F-PI2620，可能 提高在老化的海马区研究Tau的能力。此外，核磁共振技术的进步使 MTL亚区超高分辨率结构和高分辨率功能测量集合(通过7T 和3T扫描)。因此，我们建议将新的第二代Tau示踪剂整合到正在进行的 斯坦福大学现有MRI和脑脊液数据对衰老的神经成像研究(PI：Anthony Wagner，R01AG048076) 使内嗅皮层和海马区的局部TAU能够以高分辨率进行比较 MTL完整性的衡量标准。尽管CSFTau是可用的，但这一措施并不能提供区域精确度 测量Tau在MTL中的累积，强调将Tau PET添加到重点研究中的重要性 关于MTL中与年龄相关的变化。此外，考虑到R01的父母，这笔赠款的时间框架是理想的 研究正在进行到招生过程中，允许在招生的后半部分添加Tau PET， 因此，现有的脑脊液/磁共振数据与Tau PET之间的延迟最小(≤为6个月)。总的来说，这项工作将 提高对MTL与年龄相关变化背后的病因的基本理解，影响 MTL Tau对海马区记忆机制的影响，并最终预测AD痴呆的风险。

PROJECT SUMMARY Alzheimer's disease (AD) dementia is a progressive neurodegenerative disorder that is common among older individuals and typically associated with episodic memory loss. The pathophysiological processes of AD begin decades before the emergence of clinical symptoms of dementia, providing an opportunity to understand early disease mechanisms and the contribution of this pathology to memory decline in “normal” aging. Along these lines, reductions in memory within the clinically normal range are observed across the lifespan, showing subtle but consistent decrements at each decade between the 20's and 80's. Interestingly, the two hallmark pathologies of AD, the accumulation of Tau into neurofibrillary tangles (NFTs) and beta-amyloid (Aβ) into plaques, show distinct time courses and regional involvement across the lifespan. Specifically, NFTs restricted to the entorhinal cortex are common in middle age and ubiquitous in older age (50% of 50 year olds and 90% of 70 years olds have NFTs in entorhinal cortex), whereas abnormal Aβ is uncommon in middle age but prevalent at older ages and tends to be distributed throughout cortex (10% of 60 year olds and 30% of 75 year olds). Exacerbation of NFTs in entorhinal cortex and into other portions of the medial temporal lobe (MTL) and neocortex is coupled with Aβ accumulation. Recent advances in human PET imaging now enable in vivo visualization of Tau accumulation, providing a critical opportunity to establish the impact of Tau accumulation and the synergistic interaction between Tau and Aβ on memory decline in aging. However, the ability to measure PET signal directly from the hippocampus using first generation Tau tracers, such as AV1451, have been compromised by off-target binding in the choroid plexus adjacent to the hippocampus. Recently evolving second-generation tracers that show less off-target binding to choroid plexus, such as [18]F-PI2620, may improve the ability to investigate Tau in the aging hippocampus. Moreover, advancements in MRI enable the collection of ultra high-resolution structural and high-resolution functional measures of MTL subregions (via 7T and 3T scanning). We therefore propose to incorporate a novel second-generation Tau tracer into an ongoing neuroimaging study of aging at Stanford with existing MRI and CSF data (PI: Anthony Wagner, R01AG048076) to enable the comparison of regional Tau in entorhinal cortex and the hippocampus to high-resolution measures of MTL integrity. Although CSF Tau is available, this measure does not provide a regionally precise measure of Tau accumulation in the MTL, highlighting the importance of adding Tau PET into a study focused on age-related changes in the MTL. Furthermore, the timeframe of this grant is ideal given that the R01 parent study is midway through enrollment, allowing Tau PET to be added during the second half of enrollment, resulting in minimal delay between existing CSF/MRI data and Tau PET (≤6 months). Overall, this work will improve fundamental understanding of etiologies underlying age-related changes to the MTL, the impact of MTL Tau on hippocampal mechanisms of memory, and ultimately predictive risk of AD dementia.