Couvy-Duchesne Baptiste, Frouin Vincent, Bouteloup Vincent, Koussis Nikitas, Sidorenko Julia, Jiang Jiyang, Wink Alle Meije, Lorenzini Luigi, Barkhof Frederik, Trollor Julian N, Mangin Jean-François, Sachdev Perminder S, Brodaty Henry, Lupton Michelle K, Breakspear Michael, Colliot Olivier, Visscher Peter M, Wray Naomi R
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.
Paris Brain Institute - ICM, CNRS, Inria, Inserm, AP-HP, Hôpital de la Pitié Salpêtrière, Sorbonne University, Paris, France.
Hum Brain Mapp. 2025 Feb 1;46(2):e70089. doi: 10.1002/hbm.70089.
Alzheimer's disease (AD) brain markers are needed to select people with early-stage AD for clinical trials and as quantitative endpoint measures in trials. Using 10 clinical cohorts (N = 9140) and the community volunteer UK Biobank (N = 37,664) we performed region of interest (ROI) and vertex-wise analyses of grey-matter structure (thickness, surface area and volume). We identified 94 trait-ROI significant associations, and 307 distinct cluster of vertex-associations, which partly overlap the ROI associations. For AD versus controls, smaller hippocampus, amygdala and of the medial temporal lobe (fusiform and parahippocampal gyri) was confirmed and the vertex-wise results provided unprecedented localisation of some of the associated region. We replicated AD associated differences in several subcortical (putamen, accumbens) and cortical regions (inferior parietal, postcentral, middle temporal, transverse temporal, inferior temporal, paracentral, superior frontal). These grey-matter regions and their relative effect sizes can help refine our understanding of the brain regions that may drive or precede the widespread brain atrophy observed in AD. An AD grey-matter score evaluated in independent cohorts was significantly associated with cognition, MCI status, AD conversion (progression from cognitively normal or MCI to AD), genetic risk, and tau concentration in individuals with none or mild cognitive impairments (AUC in 0.54-0.70, p-value < 5e-4). In addition, some of the grey-matter regions associated with cognitive impairment, progression to AD ('conversion'), and cognition/functional scores were also associated with AD, which sheds light on the grey-matter markers of disease stages, and their relationship with cognitive or functional impairment. Our multi-cohort approach provides robust and fine-grained maps the grey-matter structures associated with AD, symptoms, and progression, and calls for even larger initiatives to unveil the full complexity of grey-matter structure in AD.
阿尔茨海默病（AD）脑标志物对于选择早期AD患者进行临床试验以及作为试验中的定量终点指标至关重要。我们利用10个临床队列（N = 9140）和社区志愿者英国生物银行（N = 37,664），对灰质结构（厚度、表面积和体积）进行了感兴趣区域（ROI）和逐顶点分析。我们确定了94个与性状ROI显著相关的区域，以及307个不同的顶点关联簇，其中部分与ROI关联重叠。与对照组相比，AD患者的海马体、杏仁核以及内侧颞叶（梭状回和海马旁回）体积更小得到了证实，并且逐顶点分析结果提供了一些相关区域前所未有的定位信息。我们在几个皮质下区域（壳核、伏隔核）和皮质区域（顶下小叶、中央后回、颞中回、颞横回、颞下回、中央旁小叶、额上回）重复了与AD相关的差异。这些灰质区域及其相对效应大小有助于深化我们对可能驱动或先于AD中广泛脑萎缩的脑区的理解。在独立队列中评估的AD灰质评分与认知、轻度认知障碍（MCI）状态、AD转化（从认知正常或MCI进展为AD）、遗传风险以及无或轻度认知障碍个体的tau浓度显著相关（曲线下面积在0.54 - 0.70之间，p值 < 5e - 4）。此外，一些与认知障碍、进展为AD（“转化”）以及认知/功能评分相关的灰质区域也与AD相关，这揭示了疾病阶段的灰质标志物及其与认知或功能障碍的关系。我们的多队列研究方法提供了与AD、症状和进展相关的灰质结构的稳健且精细的图谱，并呼吁开展更大规模的研究以揭示AD中灰质结构的全部复杂性。
