Younes Laurent, Albert Marilyn, Moghekar Abhay, Soldan Anja, Pettigrew Corinne, Miller Michael I
Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, United States.
Department of Neurology, Johns Hopkins University, Baltimore, MD, United States.
Front Aging Neurosci. 2019 Apr 2;11:74. doi: 10.3389/fnagi.2019.00074. eCollection 2019.
Several models have been proposed for the evolution of Alzheimer's disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. All nine measures had significant changepoints, all of which preceded symptom onset, however, the timing of these changepoints varied considerably. A single measure, CSF t-tau, had an early changepoint (34 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a 6-year time difference between the right and left side (respectively nine and 3 years prior to symptom onset). These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.
针对阿尔茨海默病（AD）生物标志物的演变，已经提出了几种模型。本研究的目的是确定AD临床前期一系列生物标志物中的变化点。我们检测了306名认知正常个体的九项指标，这些指标基于脑脊液（CSF）、磁共振成像（MRI）和认知测试，其中一部分个体随后进展到AD的症状期。使用变化点模型来确定哪些指标相对于临床症状发作在斜率上有显著变化。所有九项指标都有显著的变化点，且均在症状发作之前出现，然而，这些变化点的时间差异很大。单一指标脑脊液总tau蛋白（CSF t-tau）有一个早期变化点（症状发作前34年）。一组指标，包括其余的脑脊液指标（脑脊液β淀粉样蛋白和磷酸化tau蛋白）以及所有认知测试，在症状发作前10 - 15年有变化点。第二组由内侧颞叶形状综合指标组成，左右两侧存在6年的时间差异（分别在症状发作前9年和3年）。这些发现突出了症状发作前大脑中AD病理积累的漫长时期。有几个重要发现，包括认知方面的早期变化和MRI结果的左右差异。需要进一步的研究来阐明它们的意义。
