From the Lothian Birth Cohorts Group, Department of Psychology (E.L.S.C., S.M.M., S.E.H., M.d.C.V.H., M.A.H., J.M.W., I.J.D., R.E.M., S.R.C.), Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer (E.L.S.C., A.J.S., R.E.M.), Centre for Clinical Brain Sciences (E.L.S.C., S.M.M., M.d.C.V.H., M.E.B., J.M.W., H.C.W.), UK Dementia Research Institute, Edinburgh Medical School (A.J.S., V.E.M.), Division of Psychiatry, Royal Edinburgh Hospital (C.G., M.A.H., H.C.W.), and The Queen's Medical Research Institute, Edinburgh BioQuarter (V.E.M.), University of Edinburgh, UK.
Neurology. 2021 Dec 7;97(23):e2340-e2352. doi: 10.1212/WNL.0000000000012997. Epub 2021 Nov 17.
To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes.
At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation-serum C-reactive protein (CRP)-and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation-brain health associations; mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning.
We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = -0.197, 95% confidence interval [CI] -0.28 to -0.12, = 8.42 × 10), gray matter volume (β = -0.200, 95% CI -0.28 to -0.12, = 1.66 × 10), and white matter volume (β = -0.150, 95% CI -0.23 to -0.07, = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP-cognitive association (up to 29.7%), dependent on lifestyle and health factors.
These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status.
This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.
通过比较 C 反应蛋白的表观遗传和血清生物标志物，研究与认知老化相关的慢性炎症，并探讨其与神经影像学和认知结果的关系。
在基线时，参与者（n=521）认知正常，年龄在 73 岁左右（平均 72.4，标准差 0.716），并具有炎症、血管风险（心血管疾病史、高血压、糖尿病、吸烟、饮酒、体重指数）和神经影像学（结构和弥散 MRI）数据。通过传统的外周炎症标志物-血清 C 反应蛋白（CRP）和表观遗传标志物（CRP 的 DNA 甲基化[DNAm]特征）来量化基线炎症状态。使用线性模型来研究炎症与脑健康之间的关联；进行中介分析以探究慢性炎症、脑结构和认知功能之间的关系。
我们证明 DNAm CRP 与脑健康结果的相关性明显（平均强 6.4 倍）优于血清 CRP。DNAm CRP 与总脑容量（β=-0.197，95%置信区间[CI] -0.28 至 -0.12， =8.42×10）、灰质容量（β=-0.200，95% CI -0.28 至 -0.12， =1.66×10）和白质容量（β=-0.150，95% CI -0.23 至 -0.07， =0.001）和区域性脑萎缩有关。我们还发现 DNAm CRP 与整体和特定领域（速度、视空间和记忆）认知功能呈负相关，并且脑结构部分介导了 CRP 与认知的这种关联（高达 29.7%），这取决于生活方式和健康因素。
这些结果支持慢性炎症可能导致神经退行性脑改变的假说，这种改变是导致晚年认知能力差异的基础，并强调了 DNAm 标志物作为慢性炎症状态指标的潜力。
本研究提供了 II 级证据，表明 CRP 水平的 DNAm 特征与脑健康结果的相关性强于血清 CRP 水平。
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