DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging.
DNA Methylation and Protein Markers of Chronic Inflammation and Their Associations With Brain and Cognitive Aging.
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DOI：
10.1212/wnl.0000000000012997
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发表时间：
2021-12-07
期刊：
影响因子：
9.9
通讯作者：
Cox SR
中科院分区：
文献类型：
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作者：
Conole ELS;Stevenson AJ;Muñoz Maniega S;Harris SE;Green C;Valdés Hernández MDC;Harris MA;Bastin ME;Wardlaw JM;Deary IJ;Miron VE;Whalley HC;Marioni RE;Cox SR
通过比较C-反应蛋白的表观遗传和血清生物标志物及其与神经影像学和认知结果的相关性，研究慢性炎症与认知老化的关系。基线时，参与者（n = 521）认知正常，年龄约73岁（平均72.4，SD 0.716），并有炎症，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）数据可用。通过外周炎症的传统测量-血清C-反应蛋白（CRP）-和表观遗传测量（CRP的DNA甲基化[DNAm]签名）来量化基线炎症状态。使用线性模型来检查炎症-大脑健康关联;进行中介分析以询问慢性炎症、大脑结构和认知功能之间的关系。我们证明，DNAm CRP显示出显着（平均6.4倍）更强的关联与大脑健康的结果比血清CRP。DNAm CRP与总脑容量相关（β = −0.197，95%置信区间[CI] −0.28至−0.12，pFDR = 8.42 × 10−6），灰质体积（β = −0.200，95% CI −0.28至−0.12，pFDR = 1.66 × 10−5）、白色物质体积（β = −0.150，95% CI −0.23至−0.07，pFDR = 0.001）和局部脑萎缩。我们还发现，DNAm CRP与全球和特定领域（速度，视觉空间和记忆）的认知功能呈负相关，并且大脑结构部分介导这种CRP-认知关联（高达29.7%），取决于生活方式和健康因素。这些结果支持了慢性炎症可能导致神经退行性脑变化的假设，这些变化是晚年认知能力差异的基础，并突出了DNA m代表指数慢性炎症状态的潜力。这项研究提供了II类证据，证明CRP水平的DNA标记比血清CRP水平与脑健康结果更密切相关。
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, pFDR = 8.42 × 10−6), gray matter volume (β = −0.200, 95% CI −0.28 to −0.12, pFDR = 1.66 × 10−5), and white matter volume (β = −0.150, 95% CI −0.23 to −0.07, pFDR = 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.