Importance The diagnostic performance of second-generation tau positron emission tomographic (PET) tracers is not yet known.

Objective To examine the novel tau PET tracer RO948 F 18 ([¹⁸F]RO948) performance in discriminating Alzheimer disease (AD) from non-AD neurodegenerative disorders.

Design, Setting, and Participants In this diagnostic study, 613 participants in the Swedish BioFINDER-2 study were consecutively enrolled in a prospective cross-sectional study from September 4, 2017, to August 28, 2019. Participants included 257 cognitively unimpaired controls, 154 patients with mild cognitive impairment, 100 patients with AD dementia, and 102 with non-AD neurodegenerative disorders. Evaluation included a comparison of tau PET tracer [¹⁸F]RO948 with magnetic resonance imaging (MRI) and cerebrospinal fluid and a head-to-head comparison between [¹⁸F]RO948 and flortaucipir F 18 ([¹⁸F]flortaucipir) in patients with semantic variant primary progressive aphasia (svPPA).

Exposures [¹⁸F]RO948 (all patients) and [¹⁸F]flortaucipir (3 patients with svPPA) tau PET; MRI (hippocampal volume, composite temporal lobe cortical thickness, whole-brain cortical thickness) and cerebrospinal fluid measures (p-tau181 and amyloid Aβ42 and Aβ40 ratio[Aβ42/Aβ40], and Aβ42/p-tau181 ratio).

Main Outcomes and Measures Standard uptake value ratios (SUVRs) in 4 predefined regions of interest (ROIs) reflecting Braak staging scheme for tau pathology and encompass I-II (entorhinal cortex), III-IV (inferior/middle temporal, fusiform gyrus, parahippocampal cortex, and amygdala), I-IV, and V-VI (widespread neocortical areas), area under the receiver operating characteristic curve (AUC) values, and subtraction images between [¹⁸F]RO948 and [¹⁸F]flortaucipir.

Results Diagnostic groups among the 613 participants included cognitively unimpaired (mean [SD] age, 65.8 [12.1] years; 117 men [46%]), mild cognitive impairment (age, 70.8 [8.3] years; 82 men [53%]), AD dementia (age, 73.5 [6.7] years; 57 men [57%]), and non-AD disorders (age, 70.5 [8.6] years; 41 men [40%]). Retention of [¹⁸F]RO948 was higher in AD dementia compared with all other diagnostic groups. [¹⁸F]RO948 could distinguish patients with AD dementia from individuals without cognitive impairment and those with non-AD disorders, and the highest AUC was obtained using the I-IV ROI (AUC = 0.98; 95% CI, 0.96-0.99 for AD vs no cognitive impairment and AUC = 0.97; 95% CI, 0.95-0.99 for AD vs non-AD disorders), which outperformed MRI (highest AUC = 0.91 for AD vs no cognitive impairment using whole-brain thickness, and AUC = 0.80 for AD vs non-AD disorders using temporal lobe thickness) and cerebrospinal fluid measures (highest AUC = 0.94 for AD vs no cognitive impairment using Aβ42/p-tau181, and AUC = 0.93 for AD vs non-AD disorders using Aβ42/Aβ40). Generally, tau PET positivity using [¹⁸F]RO948 was observed only in Aβ-positive cases or in MAPT R406W mutation carriers. Retention of [¹⁸F]RO948 was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [¹⁸F]flortaucipir.

Conclusions and Relevance In this study, elevated [¹⁸F]RO948 SUVRs were most often seen among Aβ-positive cases, which suggests that [¹⁸F]RO948 has high specificity for AD-type tau and highlights its potential as a diagnostic marker in the differential diagnosis of AD.

重要性 第二代tau正电子发射断层扫描（PET）示踪剂的诊断性能尚不清楚。

目的 探讨新型tau PET示踪剂RO948 F 18（[ ¹⁸ F] RO948）在区分阿尔茨海默病（AD）和非AD神经退行性疾病中的作用。

设计，背景和参与者 在该诊断研究中，瑞典BioFINDER-2研究的613名参与者从2017年9月4日至2019年8月28日连续参加了一项前瞻性横断面研究。参与者包括257名无认知障碍的对照，154名轻度认知障碍患者，100例AD痴呆和102例非AD神经退行性疾病。评价包括将tau PET示踪剂[ ¹⁸ F] RO948与磁共振成像（MRI）和脑脊髓液进行比较，并对[ ¹⁸ F] RO948和氟罗西吡F 18（[ ¹⁸ F] flortaucipir）进行头对头比较。具有语义变异的原发性进行性失语症（svPPA）。

暴露于 [ ¹⁸ F] RO948（所有患者）和[ ¹⁸ F] flortaucipir（3例svPPA）的tau PET；MRI（海马体积，颞叶复合皮质厚度，全脑皮质厚度）和脑脊液量度（p-tau181与淀粉样蛋白Aβ42和Aβ40的比率[Aβ42/Aβ40]和Aβ42/ p-tau181的比率）。

主要结果和措施 4个预定义的关注区域（ROI）中的标准摄取值比率（SUVR），反映了tau病理学的Braak分期方案，涵盖I-II（肠内皮层），III-IV（下/中颞叶，梭状回，海马旁）皮层和杏仁核），I-IV和V-VI（广泛的新皮层区域），接收器工作特征曲线（AUC）值下方的区域，以及[ ¹⁸ F] RO948和[ ¹⁸ F] flortaucipir之间的相减图像。

结果 613名参与者中的诊断组包括认知能力未受损（平均[SD]年龄为65.8 [12.1]岁； 117名男性[46％]），轻度认知障碍（年龄为70.8 [8.3]岁； 82名男性[53％]） ，AD痴呆（年龄73.5 [6.7]岁； 57名男性[57％]）和非AD疾病（年龄70.5 [8.6]岁； 41男性[40％]）。与所有其他诊断组相比，AD痴呆患者的[ ¹⁸ F] RO948保留率更高。[ ¹⁸F] RO948可以将AD痴呆患者与没有认知障碍的患者和非AD障碍的患者区分开，并且使用I-IV ROI可获得最高的AUC（AUC = 0.98； 95％CI，AD为0.96-0.99）认知功能障碍和AUC = 0.97； 95％CI，AD与非AD障碍相比为0.95-0.99），其优于MRI（AD最高AUC = 0.91，而使用全脑厚度则无认知障碍，AD与AUC = 0.80使用颞叶厚度的非AD疾病）和脑脊液测量（AD最高AUC = 0.94，而使用Aβ42/ p-tau181则无认知障碍，ADC AUC = 0.93 vs使用Aβ42/Aβ40的非AD疾病）。通常，仅在Aβ阳性病例或MAPT R406W突变携带者中观察到使用[ ¹⁸ F] RO948的tau PET阳性。保留[svPPA患者未明确表达¹⁸ F] RO948，头对头比较显示，颞叶摄取低于[ ¹⁸ F] flortaucipir。

结论与相关性 在这项研究中，[ ¹⁸ F] RO948 SUVRs在Aβ阳性病例中最常见，这表明[ ¹⁸ F] RO948对AD型tau蛋白具有高度特异性，并突出了其作为A型阳性tau蛋白的诊断标志物的潜力。 AD的鉴别诊断。