1 Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Neuroscience Center, Samsung Medical Center, Seoul, Korea.
3 Department of Biomedical Engineering, Hanyang University, Seoul, Korea.
Brain. 2016 Sep;139(Pt 9):2516-27. doi: 10.1093/brain/aww148. Epub 2016 Jun 21.
SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-β and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-β and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-β and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized β = -0.79, P < 0.001; visual memory test, unstandardized β = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized β = -0.05, P = 0.002; Stroop colour test, unstandardized β = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized β = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized β = 0.21, P = 0.010) and time-varying nodal efficiency (standardized β = 0.17, P = 0.024). Time-varying lacune number (standardized β = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized β = 0.17, P = 0.021). Finally, time-varying lacune number (β = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized β = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-β and lacunes have distinct paths, and that amyloid-β or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-β and lacunes in therapeutic strategies aimed at ameliorating cognitive decline.
请科恩 DOI101093/AWW183 查看本文的科学评论：β-淀粉样蛋白和脑小血管病是导致老年人认知障碍的两个主要原因。然而，导致β-淀粉样蛋白和脑小血管病如何确切影响认知障碍的潜在机制仍不清楚。我们研究了β-淀粉样蛋白和腔隙对包括结构网络和皮质厚度在内的下游成像标志物的影响，进一步分析了它们对认知轨迹的相对影响。我们前瞻性地招募了 117 名轻度认知障碍患者（45 名遗忘型和 72 名皮质下血管型），其中 83 名患者在 3 年内接受了年度随访，包括神经心理学测试和脑磁共振成像，87 名患者接受了第二次匹兹堡化合物 B 正电子发射断层扫描分析。分析了基于弥散张量成像的结构网络和皮质厚度。我们使用线性混合效应回归模型评估了成像标志物对认知下降的影响。时变匹兹堡化合物 B 摄取与颞顶叶变薄有关，与记忆下降相关（言语记忆测试，未标准化 β=-0.79，P<0.001；视觉记忆测试，未标准化 β=-2.84，P=0.009）。时变腔隙数与额顶叶网络中断或变薄的程度有关，进一步影响额执行功能下降（数字跨度后向测试，未标准化 β=-0.05，P=0.002；斯特鲁普颜色测试，未标准化 β=-0.94，P=0.008）。在分析的多个成像标志物中，匹兹堡化合物 B 摄取和腔隙数量与记忆下降和额执行功能下降的相关性最大：时变匹兹堡化合物 B 摄取（标准化 β=-0.25，P=0.010）对视觉记忆测试的影响最强，其次是时变颞顶叶厚度（标准化 β=0.21，P=0.010）和时变节点效率（标准化 β=0.17，P=0.024）。时变腔隙数（标准化 β=-0.25，P=0.014）对时变数字跨度后向测试的影响最强，其次是时变节点效率（标准化 β=0.17，P=0.021）。最后，时变腔隙数（β=-0.22，P=0.034）对时变斯特鲁普颜色测试的影响最强，其次是时变额叶厚度（标准化 β=0.19，P=0.026）。我们的多模态成像分析表明，与β-淀粉样蛋白和腔隙相关的认知轨迹具有不同的路径，而β-淀粉样蛋白或腔隙对认知下降的影响最大。我们的结果为针对β-淀粉样蛋白和腔隙的靶向治疗策略提供了依据，旨在改善认知下降。
