Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.
Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA; Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA; College of Science, Health, Engineering and Education, Murdoch University, Perth, Australia.
Brain Behav Immun. 2021 Jul;95:178-189. doi: 10.1016/j.bbi.2021.03.015. Epub 2021 Mar 15.
Systemic inflammation has been increasingly implicated in the pathogenesis of Alzheimer's disease (AD), yet the mechanistic and temporal specificity of this relationship is poorly understood. We aimed to characterize the cross-sectional and longitudinal associations between peripheral inflammatory biomarkers, cognition, and Aβ deposition in oldest-old cognitively unimpaired (CU) adults.
A large sample of 139 CU older adults (mean age (range) = 85.4 (82-95)) underwent neuropsychological testing, Pittsburgh compound-B (PiB)-PET imaging and structural MRI. Hierarchical regression models examined associations between circulating inflammatory biomarkers (Interleukin-6 (IL-6), soluble Tumor Necrosis Factor receptors 1 and 2 (sTNFr1 and sTNFr2), soluble cluster of differentiation 14 (sCD14), C-reactive protein (CRP)), cognition, and global and regional Aβ deposition at baseline and over follow-up. Indices of preclinical disease, including pathologic Aβ status and hippocampal volume, were incorporated to assess conditional associations.
At baseline evaluation, higher concentrations of IL-6 and sTNFr2 were associated with greater global Aβ burden in those with lower hippocampal volume. In longitudinal models, IL-6 predicted subsequent conversion to MCI and both IL-6 and CRP predicted greater change in global and regional Aβ deposition specifically among participants PiB-positive at baseline. These relationships withstood adjustment for demographic factors, anti-hypertensive medication use, history of diabetes, heart disease, APOE ε4 carrier status, and white matter lesions.
In a large prospective sample of CU adults aged 80 and over, peripheral inflammatory biomarkers were associated with and predictive of the progression of Aβ deposition. This was specific to those with biomarker evidence of preclinical AD at baseline, supporting recent evidence of disease-state-dependent differences in inflammatory expression profiles. Chronic, low-level systemic inflammation may exacerbate the deposition of Aβ pathology among those with emerging disease processes, and place individuals at a higher risk of developing clinically significant cognitive impairment.
全身性炎症在阿尔茨海默病（AD）的发病机制中越来越受到关注，但这种关系的机制和时间特异性还知之甚少。我们旨在描述认知正常（CU）的高龄老年人中，外周炎症生物标志物与认知功能和 Aβ 沉积之间的横断面和纵向相关性。
我们对 139 名认知正常的高龄老年人（平均年龄（范围）=85.4（82-95））进行了神经心理学测试、匹兹堡化合物-B（PiB）-PET 成像和结构 MRI。分层回归模型检验了循环炎症生物标志物（白细胞介素-6（IL-6）、可溶性肿瘤坏死因子受体 1 和 2（sTNFr1 和 sTNFr2）、可溶性 CD14、C 反应蛋白（CRP））与认知功能和基线及随访期间的整体和区域性 Aβ 沉积之间的关系。纳入了包括病理 Aβ 状态和海马体积在内的疾病前期指标，以评估条件相关性。
在基线评估中，IL-6 和 sTNFr2 浓度较高与海马体积较小者的整体 Aβ 负担增加有关。在纵向模型中，IL-6 预测了随后向 MCI 的转化，而 IL-6 和 CRP 预测了基线时 PiB 阳性者的整体和区域性 Aβ 沉积的变化更大。这些关系在调整了人口统计学因素、抗高血压药物使用、糖尿病、心脏病、APOE ε4 携带者状态和白质病变后仍然存在。
在一项针对 139 名年龄在 80 岁及以上的认知正常成年人的大型前瞻性研究中，外周炎症生物标志物与 Aβ 沉积的进展相关，且可预测其进展。这与基线时具有疾病前期 AD 生物标志物证据的患者有关，支持了炎症表达谱在疾病状态依赖性差异的最新证据。慢性、低水平的全身性炎症可能会加剧那些出现疾病进程的患者的 Aβ 病理沉积，并使个体面临更高的发展为临床显著认知障碍的风险。
