Department of Radiology, Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY, United States.
Department of Radiology, Brain Health Imaging Institute, Weill Cornell Medicine, New York, NY, United States.
Neurosci Lett. 2024 Sep 25;840:137943. doi: 10.1016/j.neulet.2024.137943. Epub 2024 Aug 15.
One of the pathologic hallmarks of Alzheimer's disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases. Building upon increased between-network connectivity, our study hypothesizes that this increase may play a critical role in facilitating tau spread in early stages. We conducted a longitudinal study over two to three years intervals on a cohort of 46 healthy elderly participants (mean age 64.23 ± 3.15 years, 26 females). Subjects were examined clinically and utilizing advanced imaging techniques that included resting-state functional MRI (rs-fMRI), structural magnetic resonance imaging (MRI), and a second-generation positron emission tomography (PET) tau tracer, 18F-MK6240. Through unsupervised agglomerative clustering and increase in between-network connectivity, we successfully identified individuals at increased risk of future tau elevation and AD progression. Our analysis revealed that individuals with increased between-network connectivity are more likely to experience more future tau deposition, entorhinal cortex thinning, and lower selective reminding test (SRT) delayed scores. Additionally, in the limbic network, we found a strong association between tau progression and increased between-network connectivity, which was mainly driven by beta-amyloid (Aβ) positive participants. These findings provide evidence for the hypothesis that an increase in between-network connectivity predicts future tau deposition and AD progression, also enhancing our understanding of AD pathogenesis in the preclinical stages.
阿尔茨海默病（AD）的病理标志之一是神经纤维缠结tau。尽管我们知道 tau 通常起源于内侧颞叶（MTL），但驱动 tau 扩散到 MTL 之外的机制仍不清楚。新出现的证据揭示了衰老和临床前 AD 期间功能连接变化的不同模式：虽然网络内连接减少，但网络间连接增加。基于增加的网络间连接，我们的研究假设这种增加可能在促进早期 tau 扩散中发挥关键作用。我们对 46 名健康老年人（平均年龄 64.23 ± 3.15 岁，26 名女性）进行了为期两到三年的纵向研究。对受试者进行了临床检查，并利用包括静息态功能磁共振成像（rs-fMRI）、结构磁共振成像（MRI）和第二代正电子发射断层扫描（PET）tau 示踪剂 18F-MK6240 在内的先进成像技术进行了检查。通过无监督的凝聚聚类和网络间连接的增加，我们成功地确定了未来 tau 升高和 AD 进展风险增加的个体。我们的分析表明，网络间连接增加的个体更有可能经历更多的未来 tau 沉积、内嗅皮层变薄和选择性回忆测试（SRT）延迟分数降低。此外，在边缘网络中，我们发现 tau 进展与网络间连接增加之间存在很强的关联，这主要是由β-淀粉样蛋白（Aβ）阳性参与者驱动的。这些发现为以下假设提供了证据，即网络间连接的增加预测未来 tau 沉积和 AD 进展，也增强了我们对临床前阶段 AD 发病机制的理解。
