18F-MK-6240 PET 用于早期和晚期检测神经纤维缠结。

18F-MK-6240 PET for early and late detection of neurofibrillary tangles.

机构信息

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer's Disease ResearchUnit, McGill University, Montreal, Canada.

Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, McGill University, Montreal, Canada.

出版信息

Brain. 2020 Sep 1;143(9):2818-2830. doi: 10.1093/brain/awaa180.

Abstract

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future.

摘要

tau 神经纤维缠结的 Braak 阶段已被纳入阿尔茨海默病的神经病理学诊断标准。预计使用脑成像进行 Braak 分期可以根据个体的 tau 沉积模式对存活个体进行分层,这对于临床试验和实践可能至关重要。然而,以前使用第一代 tau PET 试剂的研究表明,在对应于早期 Braak 组织病理学阶段的区域(约 20%的认知正常老年人在对应于 Braak I-II 的区域有 tau 沉积)中,tau 病理学的检测灵敏度较低,而在尸检队列中报告的灵敏度约为 80-90%。在这里,我们测试了新型高亲和力 tau 缠结示踪剂 18F-MK-6240 是否可以更好地识别 tau 积累早期阶段的个体。为此,我们研究了 301 名个体(30 名认知正常的年轻人,138 名认知正常的老年人,67 名轻度认知障碍患者,54 名阿尔茨海默病痴呆患者和 12 名额颞叶痴呆患者),他们接受了淀粉样蛋白-β 18F-NAV4694、tau 18F-MK-6240、MRI 和临床评估。在示踪剂注射后 90-110 分钟采集 18F-MK-6240 标准化摄取值比图像。18F-MK-6240 以较高的准确度(约 85-100%)区分阿尔茨海默病痴呆与轻度认知障碍和额颞叶痴呆。18F-MK-6240 在我们的人群中再现了与 Braak 提出的六个层次阶段一致的拓扑模式。认知和淀粉样蛋白-β 状态解释了大部分 Braak 阶段的变异性(P < 0.0001,R2 = 0.75)。没有一个感兴趣的区域标准化摄取值比能准确地将个体分为六个拓扑 Braak 阶段。68%的认知正常的老年人淀粉样蛋白-β 阳性和 37%的认知正常的老年人淀粉样蛋白-β 阴性患者至少在颞叶前皮质(Braak I)有 tau 沉积。仅在颞叶前皮质沉积的 tau 与更高的淀粉样蛋白-β、神经退行性变和认知障碍患病率相关(P < 0.0001)。与疾病阶段相关。使用高亲和力示踪剂进行的 18F-MK-6240 成像的 Braak 六阶段分层模型提示,在临床前和有症状的个体中,tau 积累的早期和晚期以及疾病阶段均有指标。使用高亲和力示踪剂进行 tau PET Braak 分期有可能在不久的将来被纳入阿尔茨海默病患者的活体检 。

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