Qiao Yuan, Zhao Lei, Cong Chaohua, Li Yuna, Tian Shan, Zhu Xirui, Yang Junting, Cao Shanshan, Li Panlong, Su Jingjing
From the Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Qiao, Zhao, Cong, Y. Li, Tian, Yang, Cao, Su); the School of Electrical and Information Engineering, Zhengzhou University of Light Industry, Zhengzhou, China (Zhu); the Department of Medical Imaging, Henan Provincial People's Hospital & Zhengzhou University People's Hospital, Zhengzhou, China (P. Li).
From the Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Qiao, Zhao, Cong, Y. Li, Tian, Yang, Cao, Su); the School of Electrical and Information Engineering, Zhengzhou University of Light Industry, Zhengzhou, China (Zhu); the Department of Medical Imaging, Henan Provincial People's Hospital & Zhengzhou University People's Hospital, Zhengzhou, China (P. Li)
J Psychiatry Neurosci. 2025 Jan 23;50(1):E45-E56. doi: 10.1503/jpn.240039. Print 2025 Jan-Feb.
White matter damage is closely associated with cognitive and psychiatric symptoms and is prevalent in cerebral small vessel disease (CSVD); although the pathophysiological mechanisms involved in CSVD remain elusive, inflammation plays a crucial role. We sought to investigate the relationship between systemic inflammation markers and imaging markers of CVSD, namely white matter hyperintensity (WMH) and microstructural injury.
We conducted a study involving both cross-sectional and longitudinal data from the UK Biobank Cohort. We performed multiple linear regression analyses, adjusted for potential confounders, to explore the associations between systemic inflammation markers (e.g., systemic immune-inflammation index [SII], neutrophil-to-lymphocyte ratio [NLR], C-reactive protein [CRP] levels, monocyte count, neutrophil count) and macro- and microstructural white matter injury, as markers of CSVD. We performed Mendelian randomization analysis to investigate the genetically predictive effect of monocytes on WMH, as well as mediation analysis to clarify whether inflammatory markers affected cognitive function via white matter injury.
We included 36 411 participants (mean age 54.8 ± 7.5 yr, 51.9% female) from the UK Biobank Cohort. We found that SII was significantly associated with both WMH and microstructural injury markers (fractional anisotropy, mean diffusivity, intracellular volume fraction, and isotropic compartment volume fraction [ISOVF]), and the neutrophil-to-lymphocyte ratio was significantly associated with WMH and some markers of microstructural injury (mean diffusivity and ISOVF). Our analysis revealed that the CRP level was significantly associated with WMH and WMH progression but not with microstructural injury. We also demonstrated that monocyte count was significantly associated with WMH and ISOVF, and that neutrophil count was significantly associated with WMH, mean diffusivity, and ISOVF. In 2-sample Mendelian randomization analyses, we found positive associations between genetic determinants of monocytes and WMH. The mediating role of WMH suggested that a higher SII value and monocyte count could contribute to cognitive impairment through white matter injury.
Although the study includes both cross-sectional and longitudinal components, the sample size for the longitudinal aspect is limited, and the use of blood biomarkers from a single timepoint is also a limitation of this research.
The SII and neutrophil-to-lymphocyte ratio may be early detection markers for white matter damage in patients with CSVD, whereas the CRP level is more closely associated with disease severity and progression. Our findings highlight the clinical relevance of systemic inflammation markers with white matter macro- and microstructural injuries, revealing that systemic inflammation is likely involved in the mechanism of early white matter injury among patients with CSVD.
白质损伤与认知和精神症状密切相关，在脑小血管病（CSVD）中普遍存在；尽管CSVD所涉及的病理生理机制仍不清楚，但炎症起着关键作用。我们试图研究全身炎症标志物与CSVD的影像学标志物之间的关系，即白质高信号（WMH）和微观结构损伤。
我们进行了一项研究，纳入了英国生物银行队列的横断面和纵向数据。我们进行了多元线性回归分析，并对潜在混杂因素进行了调整，以探讨全身炎症标志物（如全身免疫炎症指数[SII]、中性粒细胞与淋巴细胞比值[NLR]、C反应蛋白[CRP]水平、单核细胞计数、中性粒细胞计数）与作为CSVD标志物的宏观和微观结构白质损伤之间的关联。我们进行了孟德尔随机化分析，以研究单核细胞对WMH的遗传预测作用，并进行中介分析，以阐明炎症标志物是否通过白质损伤影响认知功能。
我们纳入了来自英国生物银行队列的36411名参与者（平均年龄54.8±7.5岁，51.9%为女性）。我们发现SII与WMH和微观结构损伤标志物（分数各向异性、平均扩散率、细胞内体积分数和各向同性隔室体积分数[ISOVF]）均显著相关，中性粒细胞与淋巴细胞比值与WMH和一些微观结构损伤标志物（平均扩散率和ISOVF）显著相关。我们的分析显示，CRP水平与WMH和WMH进展显著相关，但与微观结构损伤无关。我们还证明，单核细胞计数与WMH和ISOVF显著相关，中性粒细胞计数与WMH、平均扩散率和ISOVF显著相关。在两样本孟德尔随机化分析中，我们发现单核细胞的遗传决定因素与WMH之间存在正相关。WMH的中介作用表明，较高的SII值和单核细胞计数可能通过白质损伤导致认知障碍。
尽管该研究包括横断面和纵向部分，但纵向方面的样本量有限，并且使用来自单个时间点的血液生物标志物也是本研究的一个局限性。
SII和中性粒细胞与淋巴细胞比值可能是CSVD患者白质损伤的早期检测标志物，而CRP水平与疾病严重程度和进展的关系更为密切。我们的研究结果突出了全身炎症标志物与白质宏观和微观结构损伤的临床相关性，揭示了全身炎症可能参与CSVD患者早期白质损伤的机制。
