Department of Cybernetics, Faculty of Electrical Engineering, Czech Technical University in Prague, Prague, Czech Republic.
Department of Biomedical Engineering and Assistive Technology, Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University in Prague, Prague, Czech Republic.
Brain. 2023 May 2;146(5):2075-2088. doi: 10.1093/brain/awac385.
Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer's disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer's disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer's disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer's disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer's disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer's disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer's disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer's disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer's disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.
先前的研究表明，在阿尔茨海默病痴呆症和轻度认知障碍患者中，梅内尔特胆碱能核及其白质投射受到影响。然而，目前尚不清楚这些改变是否可以在有主观认知下降的个体中发现，以及它们是否比在常规脑容积测量中发现的改变更为明显。为了解决这些问题，我们使用基于神经影像学的人类胆碱能系统的体内模型，研究了沿着阿尔茨海默病连续体的两条主要胆碱能通路的微观结构改变。我们从德国神经退行性疾病中心纵向认知障碍和痴呆症研究中纳入了 402 名参与者（52 名阿尔茨海默病患者、66 名轻度认知障碍患者、172 名主观认知下降患者和 112 名健康对照组）。我们使用增强的扩散神经影像学管道对胆碱能白质通路进行建模，该管道包括概率纤维追踪方法和先前的解剖学知识。我们在整个队列和 CSF 淀粉样β分层亚组中比较了阿尔茨海默病连续体各阶段之间、整个队列和 CSF 淀粉样β分层亚组之间胆碱能白质通路的完整性。使用接收器操作特性分析比较了这些通路完整性与海马体和梅内尔特胆碱能核的常规容积测量的区分能力。使用多变量模型研究了这些通路与认知表现的关系。我们发现，在阿尔茨海默病连续体的所有阶段，包括有主观认知下降的个体，胆碱能白质通路的完整性都显著降低。这些差异涉及主观认知下降阶段的后部胆碱能白质，在轻度认知障碍和阿尔茨海默病痴呆阶段扩展到额前白质。胆碱能通路和常规容积测量在疾病的更晚期（即轻度认知障碍和阿尔茨海默病痴呆）均显示出更高的预测能力。相比之下，与容积测量相比，胆碱能通路的完整性在区分主观认知下降与健康对照组方面更具信息量。多变量模型显示，在主观认知下降和轻度认知障碍阶段，胆碱能白质通路对记忆测试的中等贡献，但容积测量则不然。总之，我们证明了胆碱能白质通路在主观认知下降个体中已经发生改变，早于轻度认知障碍和阿尔茨海默病中发现的更广泛的改变。与海马体体积或梅内尔特胆碱能核体积等常规容积测量相比，胆碱能通路的完整性能更好地识别阿尔茨海默病的早期阶段。
