Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes
Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes
复制标题
DOI：
10.1001/jamaneurol.2020.0528
复制
发表时间：
2020-07-01
期刊：
影响因子：
29
通讯作者：
Mintun, Mark A.
中科院分区：
文献类型：
--
作者：
Fleisher, Adam S.;Pontecorvo, Michael J.;Mintun, Mark A.
重要性正电子发射断层扫描（PET）可以提高诊断准确性并确认阿尔茨海默病（AD）的潜在神经病理改变。目的确定死前[F-18]flortaucipir PET图像预测尸检ad型tau病理存在的准确性。本诊断研究（A16主要队列）于2015年10月至2018年6月在28个研究地点进行（27个在美国，1个在澳大利亚）。年龄在50岁以上、预计寿命不到6个月的绝症患者被纳入研究。所有参与者都接受了[F-18]flortaucipir PET成像，扫描结果由5名独立的核医学医师或放射科医生进行解释。还收集了16例历史收集病例的补充尸检[F-18]flortaucipir图像和病理样本。第二项研究（FR01验证研究）于2019年3月26日至4月26日进行，其中5名新读者评估了原始PET图像，以与尸检进行比较。[F-18]对flortaucipir PET图像进行视觉评估，并与免疫组织化学tau病理学进行比较。评估了flortaucipir滞留的AD tau模式与死后b3水平（Braak V期或VI期）tau积累病理模式的对应关系，以及足以满足AD高水平神经病理改变标准的淀粉样斑块的存在。成功定义为5个解读器中至少有3个高于95% CI的下限，敏感性和特异性均为50%或更高。结果共有156例患者被纳入A16研究，并接受了[F-18]flortaucipir PET成像。其中，73人在研究期间死亡，其中67人进行了有效的尸检。三例尸检被评估为检验病例，并从主要队列中剔除（n = 64）。在64例原发性队列患者中，34例（53%）为女性，62例（97%）为白人；平均（SD）年龄为82.5（9.6）岁；49人（77%）有痴呆，1人（2%）有轻度认知障碍，14人（22%）有正常认知。A16主要队列符合预先指定的成功标准。flortaucipir PET扫描预测B3级tau病理，敏感性为92.3% （95% CI, 79.7%-97.3%）至100.0% (95% CI, 91.0%-100.0%)，特异性为52.0% （95% CI, 33.5%-70.0%）至92.0% （95% CI, 75.0%-97.8%）。高水平的AD神经病变预测灵敏度为94.7% （95% CI, 82.7%-98.5%）至100.0% (95% CI, 90.8%-100.0%)，特异性为50.0% （95% CI, 32.1%-67.9%）至92.3% （95% CI, 75.9%-97.9%）。FR01验证研究也符合预定的成功标准。补充尸检数据集和3个测试案例（包括A16和FR01研究的82例患者和尸检）的加入，提高了特异性和可比较的总体准确性。在156名入组参与者中，14名（9%）经历了至少1次治疗后出现的不良事件。本研究结果提示，[F-18]flortaucipir PET成像可用于识别AD型tau病理的密度和分布以及AD神经病变的高水平存在，支持AD的神经病理学诊断。[F-18]flortaucipir正电子发射断层扫描（PET）图像的视觉读取结果是否与阿尔茨海默病tau和淀粉样蛋白病理的死后评估相符？在这项对82名患有或不患有痴呆症的个体进行的诊断研究中，[F-18]flortaucipir PET扫描的视觉读值与死后Braak阶段的皮层神经原纤维缠结和高水平的阿尔茨海默病神经病理改变相对应。本研究的结果表明，[F-18]flortaucipir PET扫描的视觉读数可以准确地支持阿尔茨海默病的病理诊断。本诊断性研究探讨了使用[F-18]flortaucipir的正电子发射断层扫描是否可以检测患有或不患有痴呆症的终末期成人的tau病理和阿尔茨海默病神经病理变化。
Importance Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective To determine the accuracy of antemortem [F-18]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [F-18]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [F-18]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures [F-18]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-beta plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results A total of 156 patients were enrolled in the A16 study and underwent [F-18]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance This study's findings suggest that PET imaging with [F-18]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.Question Do the findings of visual reads of [F-18]flortaucipir positron emission tomography (PET) images correspond with postmortem assessment of Alzheimer disease tau and amyloid pathologies? Findings In this diagnostic study of 82 individuals with or without dementia, visual reads of [F-18]flortaucipir PET scans corresponded with postmortem Braak stages V and VI levels of cortical neurofibrillary tangles and high levels of Alzheimer disease neuropathological change. Meaning Findings from this study suggest that visual reads of [F-18]flortaucipir PET scans may accurately support a pathological diagnosis of Alzheimer disease.This diagnostic study explores whether positron emission tomography with [F-18]flortaucipir can detect tau pathology and Alzheimer disease neuropathologic changes in terminally ill adults with or without dementia.