BACKGROUND Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer's disease, but inflammation's effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status. METHODS Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden. RESULTS Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β=-0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (β=-0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks). CONCLUSION Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.

中文翻译：

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非痴呆老年人大规模功能性脑网络中外周炎症标志物与连通性的关联

背景系统性炎症已成为认知衰退和阿尔茨海默病的危险因素，但炎症对分布式脑网络的影响尚不清楚。我们检查了五个大规模认知网络中外周炎症标志物和随后的功能连接之间的关系，并评估了皮质淀粉样蛋白和 APOE ε4 状态的调节作用。方法 对 176 名参与者（基线平均年龄：65（SD 9）岁；63% 女性；85% 认知正常，15% 轻度认知障碍（MCI )) 并结合起来得出炎症指数。大约六年后，参与者接受了静息状态功能磁共振成像以量化功能连接性；137 名参与者的一个子集还接受了 11C 匹兹堡化合物-B (PiB) PET 成像，以评估皮质淀粉样蛋白负荷。结果 使用针对人口特征和心血管危险因素调整的线性回归模型，较高的炎症指数与默认模式（β=-0.013；95% CI：-0.023，-0.003）和背侧注意网络（β =-0.017；95% CI：-0.028，-0.006）。这些关联的强度不因淀粉样蛋白状态（阳性/阴性）而异。然而，炎症指数和 APOE ε4 状态之间存在显着的相互作用，因此炎症指数较高的 ε4 阳性参与者表现出较低的连通性。炎症指数与其他大规模认知网络（Control、Limbic、和显着性/腹侧注意网络）。结论 没有痴呆的老年人，特别是 APOE ε4 阳性个体的外周促炎信号与两个大规模认知网络内的连接改变有关。