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.

中文翻译：

---

18F-MK-6240 PET用于早期和晚期检测神经原纤维缠结。

tau神经原纤维缠结的Braak阶段已被纳入阿尔茨海默氏病神经病理学诊断标准。预期使用脑成像进行的Braak分期可以根据活体个体的tau沉积模式对其进行分层，这对于临床试验和实践可能至关重要。但是，先前使用第一代tau PET试剂的研究表明，在与Braak组织病理学早期阶段相对应的区域中检测tau病理学的敏感性较低（约有20％的认知无障碍老年人在与Braak I–II相对应的区域出现tau沉积），与之相比，在尸检后队列中约占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可以更好地识别tau积累早期的个体。为此，我们研究了301个人中淀粉状蛋白β（30认知未受损伤的年轻人，138认知老年人不受损害，67轻度认知障碍，54与阿尔茨海默病性痴呆，和12额颞叶痴呆），¹⁸架F-NAV4694，头¹⁸ F- MK-6240，MRI和临床评估。示踪剂注入后90–110分钟采集了^18张F-MK-6240标准化摄取值比率图像。¹⁸ F-MK-6240可以将阿尔茨海默氏病痴呆症与轻度认知障碍和额颞叶痴呆症准确地区分开（约85-100％）。¹⁸F-MK-6240概括了Braak在98％的人口中提出的六个等级阶段的地形图。认知和淀粉样β状态解释了大多数Braak阶段的差异（P  <  0.0001，R ² = 0.75）。没有一个单一的感兴趣区域标准化吸收值比率可将个体准确地分为六个地形Braak阶段。至少在跨肠上皮皮质中，有68％的认知能力受损的老年人淀粉样β阳性和37％的认知力受损的老年人淀粉样β阴性表现出tau沉积（Braak I）。仅Tau沉积在跨肠皮质中与淀粉样β的患病率升高，神经变性和认知障碍有关（P  < 0.0001）。在对应于Braak IV–VI的区域中¹⁸ F-MK-6240沉积与神经变性的患病率最高相关，而在Braak V–VI的认知障碍患病率最高。我们的结果表明，使用¹⁸ F-MK-6240成像的六阶段Braak模型提供了临床前和有症状个体的早期和晚期tau积累以及疾病阶段的指标。使用高亲和力示踪剂的Tau PET Braak分期有可能在不久的将来用于诊断活着的阿尔茨海默氏病患者。