Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention
Neuroanatomical spread of amyloid β and tau in Alzheimer's disease: implications for primary prevention
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DOI：
10.1093/braincomms/fcaa007
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Donohue, Michael C.
中科院分区：
文献类型：
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作者：
Insel, Philip S.;Mormino, Elizabeth C.;Donohue, Michael C.
随着我们对阿尔茨海默病在症状出现前许多年开始的持续病理生理变化的理解的最新进展，现在很明显，阿尔茨海默病不能用离散的临床阶段来充分描述，而应该包括在疾病临床表现之前和基础上的一系列生物学变化。通过联合考虑所有可用生物标志物的纵向变化和临床评估，个体内的变化可以被整合为疾病进展的单一连续测量，并用于识别最早的病理生理变化。疾病时间是衡量疾病严重程度的指标，通过应用于一系列成像、生物标记物和神经心理学数据的贝叶斯潜伏期联合混合效应模型来估计。区域淀粉样β蛋白和tau PET摄取的轨迹被估计为疾病时间的函数。早期有淀粉样蛋白b摄取升高迹象的区域被用来形成早期的局部复合体，并在单独的验证样本中与常用的全球复合体进行比较。279名参与者(183名认知正常的人，61名轻度认知障碍和35名阿尔茨海默病痴呆症患者)利用可用的淀粉样β蛋白和tau PET数据估计了疾病时间。扣带回后部和楔叶前区的淀粉样β-PET摄取水平开始较高，并随着疾病时间的小幅增加而立即增加。Tau PET摄取率早期升高的部位有颞叶下部、杏仁核、颞叶上沟缘、内嗅皮层、中叶、顶叶下部和梭形回。在对188名认知正常个体的单独验证样本中，早期的局部淀粉样β-PET复合体显示，与全球复合体(P<；0.001)相比，淀粉样β蛋白的累积速率增加了120%，导致在一级预防试验设计中检测治疗效果的能力增加了60%。根据连续的疾病时间对参与者进行排序，有助于检查淀粉样蛋白b和tau病理的最早迹象。为了检测淀粉样蛋白b病理的早期变化，专注于淀粉样β蛋白积聚的最早部位，可以在早期阿尔茨海默病中产生更强大和更有效的研究设计。靶向复合体可用于重新检查淀粉样蛋白b相关研究纳入的阈值，特别是在该领域转向关注一级和二级预防的情况下。抗淀粉样蛋白b治疗的临床试验可能受益于在估计药物对淀粉样蛋白b和tau病变最小和预期短期蓄积有限的人群中淀粉样β蛋白和tau变化的药物效果时使用焦点复合体。
With recent advances in our understanding of the continuous pathophysiological changes that begin many years prior to symptom onset, it is now apparent that Alzheimer's disease cannot be adequately described by discrete clinical stages, but should also incorporate the continuum of biological changes that precede and underlie the clinical representation of the disease. By jointly considering longitudinal changes of all available biomarkers and clinical assessments, variation within individuals can be integrated into a single continuous measure of disease progression and used to identify the earliest pathophysiological changes. Disease time, a measure of disease severity, was estimated using a Bayesian latent time joint mixed-effects model applied to an array of imaging, biomarker and neuropsychological data. Trajectories of regional amyloid beta and tau PET uptake were estimated as a function of disease time. Regions with early signs of elevated amyloid b uptake were used to form an early, focal composite and compared to a commonly used global composite, in a separate validation sample. Disease time was estimated in 279 participants (183 cognitively unimpaired individuals, 61 mild cognitive impairment and 35 Alzheimer's disease dementia patients) with available amyloid beta and tau PET data. Amyloid beta PET uptake levels in the posterior cingulate and precuneus start high and immediately increase with small increases of disease time. Early elevation in tau PET uptake was found in the inferior temporal lobe, amygdala, banks of the superior temporal sulcus, entorhinal cortex, middle temporal lobe, inferior parietal lobe and the fusiform gyrus. In a separate validation sample of 188 cognitively unimpaired individuals, the early, focal amyloid beta PET composite showed a 120% increase in the accumulation rate of amyloid beta compared to the global composite (P< 0.001), resulting in a 60% increase in the power to detect a treatment effect in a primary prevention trial design. Ordering participants on a continuous disease time scale facilitates the inspection of the earliest signs of amyloid b and tau pathology. To detect early changes in amyloid b pathology, focusing on the earliest sites of amyloid beta accumulation results in more powerful and efficient study designs in early Alzheimer's disease. Targeted composites could be used to re-examine the thresholds for amyloid b-related study inclusion, especially as the field shifts to focus on primary and secondary prevention. Clinical trials of anti-amyloid b treatments may benefit from the use of focal composites when estimating drug effects on amyloid beta and tau changes in populations with minimal amyloid b and tau pathology and limited expected short-term accumulation.