Rates of tau accumulation in cognitively unimpaired older adults are subtle with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid β-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts, and how these patterns relate to amyloid burden, in order to design optimal tau endpoints for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (N = 447), the Alzheimer’s Disease Neuroimaging Initiative (N = 420), and the Harvard Aging Brain Study (N = 190), we attempt to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts, when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern – inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid β levels. For participants with highly elevated baseline amyloid β levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala, and 16% fusiform. At mildly elevated levels of baseline amyloid β, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation), to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer’s disease.

中文翻译：

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Tau 正电子发射断层扫描在临床前阿尔茨海默病中的应用

在最近的报告中，认知未受损的老年人中 tau 蛋白积累的速度很微妙，其幅度和空间模式各不相同。区域积累也可能因β淀粉样蛋白依赖性积累的程度而异。因此，需要评估多个认知未受损人群中 tau 积累的模式和一致性，以及这些模式与淀粉样蛋白负荷的关系，以便为临床试验设计最佳 tau 终点。使用三大组认知未受损的老年人进行无症状阿尔茨海默氏症的抗淀粉样蛋白治疗及其同伴研究、淀粉样蛋白风险和神经变性的纵向评估 (N = 447)、阿尔茨海默氏病神经影像计划 (N = 420) 和哈佛老龄化研究在大脑研究 (N = 190) 中，我们尝试识别 tau 蛋白积累率较高的区域，并估计这些速率在基线淀粉样蛋白沉积的连续谱上如何演变。针对多个基线淀粉样蛋白负荷范围定制的最佳区域组合作为假设的临床试验纳入标准进行了测试和验证。当单独考虑时，颞下皮层、梭状回和颞中皮层在两个纵向队列中具有最大的累积效应大小。当结合感兴趣的 tau 区域来找到复合权重以最大化 tau 随时间变化的效应大小时，两项纵向研究都表现出相似的模式——下颞叶皮层几乎完全适合β淀粉样蛋白水平轻度升高的参与者。对于基线β淀粉样蛋白水平高度升高的参与者，组合最佳复合权重为53%颞下皮层、31%杏仁核和16%梭形。在基线β淀粉样蛋白水平轻度升高的情况下，每组 200 个样本量需要 0.40-0.45 的治疗效果（tau 积累减慢 40-45%），才能为使用优化复合材料进行为期 18 个月的试验提供动力。颞叶复合和全局复合均未达到 80%（每组 200 个）的功效，且效应值低于 0.5。早期 tau 蛋白积累集中在内侧颞叶，这是由于观察到内嗅皮层是随年龄增长而出现 tau 蛋白水平异常的最初部位。然而，这些异常水平似乎并不是短期内高积累率的结果，而可能是随着年龄的增长而出现的较温和的积累率。虽然内嗅皮层在 tau 蛋白的早期出现中发挥着核心作用，但下颞叶皮层可能是临床前阿尔茨海默病中 tau 蛋白快速积累的关键区域。