Chauveau Léa, Landeau Brigitte, Dautricourt Sophie, Turpin Anne-Laure, Delarue Marion, Hébert Oriane, de La Sayette Vincent, Chételat Gaël, de Flores Robin
U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Neuropresage Team; INSERM, University of Caen Normandy; GIP Cyceron, 14000 Caen, France.
Centre mémoire ressource recherche, Hôpital des Charpennes, Hospices civils de Lyon; 69000 Lyon, France.
Brain. 2025 Jan 15. doi: 10.1093/brain/awaf008.
Curing Alzheimer's disease remains hampered by an incomplete understanding of its pathophysiology and progression. Exploring dysfunction in medial temporal lobe networks, particularly the anterior-temporal (AT) and posterior-medial (PM) systems, may provide key insights, as these networks exhibit functional connectivity alterations along the entire Alzheimer's continuum, potentially influencing disease propagation. However, the specific changes in each network and their clinical relevance across stages are not yet fully understood. This requires considering commonly used biomarkers, clinical progression, individual variability, and age confounds. Here, we leveraged monocentric longitudinal data from 261 participants spanning the adult lifespan and the Alzheimer's continuum. The sample included cognitively unimpaired adults aged 19 to 85 years (n = 209; eight out of 64 older adults over 60 were Aβ-positive) and Aβ-positive patients fulfilling diagnostic criteria for mild cognitive impairment (MCI, n = 26; 18 progressed to Alzheimer-dementia within seven years) or Alzheimer's type dementia (n = 26). Participants underwent structural and resting-state functional (f) MRI, florbetapir and FDG-PET, and global cognitive assessments, with up to three visits over a maximum period of 47 months. Network connectivity was assessed using seed-based analyses with the perirhinal and parahippocampal cortices as seeds, within data-driven masks reflecting the AT and PM networks. Generalized additive and linear mixed models were run to assess age-specific effects and Alzheimer's-related alterations. In this context, we explored various markers of pathological and clinical severity, including cerebral amyloid uptake, glucose metabolism, hippocampal volume, global cognition, diagnostic staging, and time to dementia onset. Our findings revealed distinct patterns of connectivity linked to normal aging or Alzheimer's disease. Advancing age throughout adulthood was associated with lower PM connectivity and more subtle changes in AT connectivity, while Alzheimer's disease was characterised by AT hyperconnectivity without global changes in PM connectivity. Specifically, AT connectivity was higher in MCI and Alzheimer-dementia patients compared to older controls and was positively associated with amyloid burden, glucose hypometabolism, hippocampal atrophy, and global cognitive deficits in older adults, ranging from unimpaired to demented. Additionally, higher AT connectivity correlated with faster progression to Alzheimer-dementia in MCI patients. This comprehensive approach allowed to reveal that excessive connectivity within the AT network is intrinsically linked to the pathological and clinical progression of Alzheimer's disease. These insights may guide future research to better understand cascading events leading to the disease and hold promise for developing prognostic tools and therapeutic interventions targeting these specific network alterations.
对阿尔茨海默病病理生理学和进展的不完全理解仍然阻碍着其治愈。探索内侧颞叶网络的功能障碍，特别是前颞叶（AT）和后内侧（PM）系统，可能会提供关键见解，因为这些网络在整个阿尔茨海默病连续过程中表现出功能连接改变，可能影响疾病传播。然而，每个网络的具体变化及其在各个阶段的临床相关性尚未完全了解。这需要考虑常用的生物标志物、临床进展、个体差异和年龄混杂因素。在此，我们利用了来自261名跨越成年期和阿尔茨海默病连续过程参与者的单中心纵向数据。样本包括19至85岁认知未受损的成年人（n = 209；64名60岁以上的老年人中有8名Aβ呈阳性）以及符合轻度认知障碍（MCI，n = 26；其中18名在7年内进展为阿尔茨海默病痴呆）或阿尔茨海默病型痴呆（n = 26）诊断标准的Aβ阳性患者。参与者接受了结构和静息态功能（f）MRI、氟代硼吡咯和FDG-PET检查以及整体认知评估，在最长47个月的时间内最多进行三次随访。使用以嗅周皮质和海马旁皮质为种子的基于种子的分析，在反映AT和PM网络的数据驱动掩码内评估网络连接性。运行广义相加模型和线性混合模型以评估特定年龄效应和与阿尔茨海默病相关的改变。在此背景下，我们探索了病理和临床严重程度的各种标志物，包括脑淀粉样蛋白摄取、葡萄糖代谢、海马体积、整体认知、诊断分期以及痴呆发病时间。我们的研究结果揭示了与正常衰老或阿尔茨海默病相关的不同连接模式。成年期年龄增长与PM连接性降低以及AT连接性更细微的变化相关，而阿尔茨海默病的特征是AT连接性增强，而PM连接性无整体变化。具体而言，与老年对照组相比，MCI和阿尔茨海默病痴呆患者的AT连接性更高，并且与老年人从未受损到痴呆阶段的淀粉样蛋白负荷、葡萄糖代谢减退、海马萎缩和整体认知缺陷呈正相关。此外，较高的AT连接性与MCI患者更快进展为阿尔茨海默病痴呆相关。这种综合方法揭示了AT网络内的过度连接与阿尔茨海默病的病理和临床进展内在相关。这些见解可能会指导未来的研究，以更好地理解导致该疾病的级联事件，并有望开发针对这些特定网络改变的预后工具和治疗干预措施。
