Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study
Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study
复制标题
DOI：
10.1001/jamaneurol.2019.1424
复制
发表时间：
2019-08-01
期刊：
影响因子：
29
通讯作者：
Johnson, Keith
中科院分区：
文献类型：
--
作者：
Hanseeuw, Bernard J.;Betensky, Rebecca A.;Johnson, Keith
关键点认知能力下降是否与淀粉样蛋白β或tau蛋白缠结积累有关？在这项队列研究中，包括60名正常老年人，重复进行正电子发射断层扫描测量，下颞叶新皮质中tau蛋白积累的速率与认知能力下降的速率相关。淀粉样蛋白积累与随后的tau蛋白积累相关，发现新皮质中连续的淀粉样蛋白和tau蛋白变化的序列介导了初始淀粉样蛋白与7年后测量的最终认知的关联。意义淀粉样蛋白正电子发射断层扫描可用于检测早期阿尔茨海默病病理;重复tau蛋白正电子发射断层扫描可用于跟踪疾病进展。重要性正电子发射断层扫描（PET）成像现在允许在体内可视化阿尔茨海默病（AD）的两种神经病理学标志：淀粉样蛋白β（A β）斑块和tau蛋白神经元缠结。观察它们在临床正常老年人大脑中的进行性积累对于了解导致AD的病理生理级联反应以及告知预防试验中结局指标的选择至关重要。目的评估在7年的不同观察期间测量的A β、tau蛋白和认知之间的关联。设计、设置和患者前瞻性队列研究，于2010年至2017年在马萨诸塞州波士顿的哈佛老龄化脑研究中进行。该研究招募了279名临床正常的参与者。另外90人被接触，但拒绝了研究或不符合纳入标准。在本报告中，我们分析了60名参与者的数据，这些参与者在2017年10月31日获得了多个A β和tau PET观察结果。主要结局和指标收集了3个匹兹堡化合物B-PET（A β，2010-2017）和2个flortaucipir-PET（tau，2013-2017）图像的中位数。我们使用初始PET和斜率数据，评估A β和tau的变化率，以测量认知变化。每年使用临床前阿尔茨海默氏症认知综合症（2010-2017）评估认知。年度共识会议评估进展为轻度认知障碍。结果在60名参与者中，35名女性（58%）和25名男性（42%）;入选时的中位年龄为73岁（范围65-85岁）。17名参与者（28%）表现出初始高A β负担。A β的前期升高与tau的后续变化相关（1.07 flortaucipir标准化摄取值比值[SUVr]/PiB-SUVr; 95% CI，0.13-3.46; P= 0.02）。Tau的变化与认知变化（-3.28 z评分/SUVR; 95% CI，-6.67至-0.91; P=.001）、协变基线A β和Tau相关。进展为轻度认知障碍的参与者（n=6）的Tau变化大于未进展为轻度认知障碍的参与者（n=11; 0.05 SUVr/年; 95% CI，0.03-0.07; P= 0.001）。一个系列的中介模型表明，最初的A β和最终的认知之间的关联，7年后测量，介导的连续变化A β和tau。结论和相关性我们确定了正常老年人从A β到tau再到认知的顺序变化，之后高A β和更大tau增加的参与者符合轻度认知障碍的临床标准。这些发现强调了重复tau-PET观察跟踪疾病进展的重要性，以及重复淀粉样蛋白PET观察检测最早AD病理变化的重要性。这项队列研究评估了淀粉样蛋白β、tau蛋白和认知之间的关联，在7年的不同观察期内进行测量。
Key PointsQuestionIs cognitive decline associated with amyloid-beta or tau tangles accumulation? FindingsIn this cohort study that included 60 normal older adults with repeated positron emission tomography measures, the rate of tau accumulation in the inferior temporal neocortex was associated with the rate of cognitive decline. Amyloid accumulation was associated with subsequent tau accumulation, and this sequence of successive amyloid and tau changes in neocortex was found to mediate the association of initial amyloid with final cognition, measured 7 years later. MeaningAmyloid positron emission tomography is useful to detect early Alzheimer pathology; repeated tau positron emission tomography is useful to track disease progression.ImportancePositron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-beta (A beta) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. ObjectiveTo assess the associations among A beta, tau, and cognition, measured during different observation periods for 7 years. Design, Setting, and ParticipantsProspective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple A beta and tau PET observations available on October 31, 2017. Main Outcomes and MeasuresA median of 3 Pittsburgh compound B-PET (A beta, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in A beta and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. ResultsOf the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high A beta burden. An antecedent rise in A beta was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P=.02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P=.001), covarying baseline A beta and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n=6) than in those who did not (n=11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P=.001). A serial mediation model demonstrated that the association between initial A beta and final cognition, measured 7 years later, was mediated by successive changes in A beta and tau. Conclusions and RelevanceWe identified sequential changes in normal older adults, from A beta to tau to cognition, after which the participants with high A beta with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.This cohort study assesses the associations among amyloid-beta, tau, and cognition, measured during different observation periods for 7 years.