Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA.
Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Alberta, Canada.
Brain. 2022 Sep 14;145(9):3179-3186. doi: 10.1093/brain/awac107.
Cerebral white matter hyperintensities are an important contributor to ageing brain pathology. Progression in white matter hyperintensity volume is associated with cognitive decline and gait impairment. Understanding the factors associated with white matter hyperintensity progression provides insight into pathogenesis and may identify novel treatment targets to improve cognitive health. We postulated that the immune system interaction with cerebral vessels and tissue may be associated with disease progression, and thus evaluated the relationship of blood leucocyte gene expression to progression of cerebral white matter hyperintensities. A brain MRI was obtained at baseline in 166 patients assessed for a cognitive complaint, and then repeated at regular intervals over a median of 5.9 years (interquartile range 3.5-8.2 years). White matter hyperintensity volumes were measured by semi-automated segmentation and percentage change in white matter hyperintensity per year calculated. A venous blood sample obtained at baseline was used to measure whole-genome expression by RNA sequencing. The relationship between change in white matter hyperintensity volumes over time and baseline leucocyte gene expression was analysed. The mean age was 77.8 (SD 7.5) years and 60.2% of participants were female. The median white matter hyperintensity volume was 13.4 ml (SD 17.4 ml). The mean change in white matter hyperintensity volume was 12% per year. Patients were divided in quartiles by percentage change in white matter hyperintensity volume, which was: -3.5% per year in quartile 1, 7.4% per year in quartile 2, 11.7% in quartile 3 and 33.6% per year in quartile 4. There were 148 genes associated with changing white matter hyperintensity volumes over time (P < 0.05 r > |0.2|). Genes and pathways identified have roles in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. ADAM8, CFD, EPHB4, FPR2, Wnt-B-catenin, focal adhesion kinase and SIGLEC1 were among the identified genes. The progression of white matter hyperintensity volumes over time is associated with genes involved in endothelial dysfunction, extracellular matrix remodelling, altered remyelination, inflammation and response to ischaemia. Further studies are needed to evaluate the role of peripheral inflammation in relation to rate of white matter hyperintensity progression and the contribution to cognitive decline.
脑白质高信号是导致大脑老化的重要病理学因素。脑白质高信号体积的进展与认知能力下降和步态障碍有关。了解与脑白质高信号进展相关的因素可以深入了解发病机制，并可能确定改善认知健康的新治疗靶点。我们推测，免疫系统与脑血管和组织的相互作用可能与疾病进展有关，因此评估了血液白细胞基因表达与脑白质高信号进展的关系。在 166 名因认知问题而接受评估的患者中，在基线时进行了脑部 MRI 检查，然后在中位数为 5.9 年（四分位距 3.5-8.2 年）的时间内定期重复检查。通过半自动分割测量脑白质高信号体积，并计算每年脑白质高信号的百分比变化。在基线时采集的静脉血样用于通过 RNA 测序测量全基因组表达。分析了随时间变化的脑白质高信号体积与基线白细胞基因表达之间的关系。患者的平均年龄为 77.8（SD 7.5）岁，60.2%为女性。脑白质高信号中位数为 13.4ml（SD 17.4ml）。脑白质高信号体积的平均年变化为 12%。根据脑白质高信号体积的年变化百分比，患者分为四个四分位数，分别为：第 1 四分位数为每年-3.5%，第 2 四分位数为每年 7.4%，第 3 四分位数为每年 11.7%，第 4 四分位数为每年 33.6%。有 148 个基因与随时间变化的脑白质高信号体积有关（P<0.05，r>0.2）。鉴定出的基因和途径在血管内皮功能障碍、细胞外基质重塑、脱髓鞘改变、炎症和对缺血的反应中发挥作用。ADAM8、CFD、EPHB4、FPR2、Wnt-β-catenin、粘着斑激酶和 SIGLEC1 等是鉴定出的基因之一。脑白质高信号体积随时间的进展与参与血管内皮功能障碍、细胞外基质重塑、脱髓鞘改变、炎症和对缺血反应的基因有关。需要进一步研究外周炎症与脑白质高信号进展速度的关系及其对认知能力下降的贡献。
