Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, United States of America.
Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont, United States of America.
PLoS One. 2022 Sep 9;17(9):e0274350. doi: 10.1371/journal.pone.0274350. eCollection 2022.
Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer's Disease, dementia, and cognitive disorders. We examined the association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.
与先天和适应性免疫系统相关的炎症细胞因子和趋化因子与阿尔茨海默病、痴呆和认知障碍的神经炎症有关。我们研究了 11 种与免疫和炎症反应相关的血浆蛋白（CD14、CD163、CD5L、CD56、CD40L、CXCL16、SDF1、DPP4、SGP130、sRAGE 和 MPO）与认知功能、脑 MRI 和痴呆风险之间的关联。我们确定了在第七次检查后五年内接受神经心理测试（n = 2358）或脑 MRI（n = 2100）的弗雷明汉心脏研究后代参与者，在那里获得了定量蛋白质生物标志物的血液样本；并在 10 年内对所有原因的痴呆（n = 1616）进行了随访。我们使用线性混合效应模型，根据家庭关系，研究了炎症生物标志物与神经心理测试表现和脑 MRI 体积之间的关系。我们进一步使用 Cox 比例风险模型来研究与痴呆事件的关联。假发现率 p 值用于考虑多重测试。纳入神经心理学测试和 MRI 样本的参与者平均年龄为 61 岁，54%为女性。在事件性痴呆样本中（基线时平均年龄为 68 岁），包括 124 名发生痴呆的参与者。除了已经确定的 CD14 外，我们还发现 CD40L 和髓过氧化物酶（MPO）水平升高与执行功能障碍显著相关。较高的 CD5L 水平与总脑体积（TCBV）较小显著相关，而较高的 sRAGE 水平与 TCBV 较大相关。在调整 APOE ε4 携带者状态和其他心血管危险因素后，关联仍然存在。在研究的炎症生物标志物中，没有一个与全因痴呆的发病风险显著相关。可溶性 CD40L 和 MPO 水平升高，这些标志物是免疫细胞激活的标志，与神经心理测试表现较差相关，而炎症的关键调节因子 CD5L 与总脑体积较小相关。可溶性 RAGE 水平升高，RAGE/AGE 途径的一种诱饵受体，与总脑体积较大相关。如果在其他研究中得到证实，这一数据表明激活的免疫系统参与了异常的大脑衰老。
