Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer’s disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer’s Coordinating Center cases providing three different LC measures (pigmentation, tangle density, and neuronal density), Braak staging, β-amyloid, and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density and were particularly worse at advanced Braak stages. In the context of elevated β-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD.

中文翻译：

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体内和神经病理学数据支持蓝斑完整性作为阿尔茨海默病病理学和认知衰退的指标

几项尸检研究将蓝斑 (LC) 识别为过度磷酸化 TAU 聚集的初始位点，并且随着携带 TAU 的 LC 神经元数量的增加，TAU 病理学出现在整个皮质中。通过联合使用 LC 完整性和 TAU 和淀粉样蛋白 PET 成像的专用 MRI 测量，我们旨在解决 174 名认知未受损和受损老年人的体内 LC 测量是否与阿尔茨海默病 (AD) 纤维蛋白病或认知功能障碍的初始皮质模式相关的问题具有纵向认知测量的个体。为了指导我们的解释，我们在来自 1524 个宗教秩序研究和 Rush Memory and Aging Project 的尸检数据和 2145 个国家阿尔茨海默氏症协调中心案例中验证了这些关联，这些案例提供了三种不同的 LC 测量值（色素沉着、缠结密度、和神经元密度）、Braak 分期、β-淀粉样蛋白和纵向认知测量。较低的 LC 完整性与未受损个体的内嗅皮质中 TAU 沉积升高有关，这与 LC 缠结密度和连续 Braak 分期之间的死后相关性一致。LC 色素沉着等级与 LC 神经元密度相关，但与 LC 缠结密度无关，并且在 Braak 晚期阶段尤其严重。在 β-淀粉样蛋白升高的情况下，较低的 LC 完整性和较大的皮质缠结密度与颞叶内侧以外的 TAU 负担和回顾性记忆下降有关。