Seidel Florine, Vreeken Debby, Custers Emma, Wiesmann Maximilian, Özsezen Serdar, van Duyvenvoorde Wim, Caspers Martien, Menke Aswin, Morrison Martine C, Verschuren Lars, Duering Marco, Hazebroek Eric J, Kiliaan Amanda J, Kleemann Robert
Department Medical Imaging, Anatomy, Radboud Alzheimer Center, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Geert Grooteplein 21N, 6525 EZ Nijmegen, the Netherlands.
Department of Metabolic Health Research, Netherlands Organisation for Applied Scientific Research (TNO), Sylviusweg 71, 2333 BE Leiden, the Netherlands.
Heliyon. 2024 Sep 26;10(19):e38516. doi: 10.1016/j.heliyon.2024.e38516. eCollection 2024 Oct 15.
It is unclear whether early metabolic and inflammatory aberrations in the liver are associated with detrimental changes in brain structure and cognitive function. This cross-sectional study examines putative associations between metabolic dysfunction-associated steatotic liver disease (MASLD) and brain health in 36-55 year-old participants with obesity (n = 70) from the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity). The participants underwent brain magnetic resonance imaging to study brain volumes and cortical thickness (3T MRI including T1-weighted magnetization-prepared rapid gradient-echo sequence), cerebral blood perfusion (arterial spin labeling) and white matter integrity (diffusion weighted imaging to assess mean-skeletonized mean diffusivity and fluid-attenuated inversion recovery to detect the presence of white matter hyperintensities (WMH)). The participants additionally performed neuropsychological tests to assess global cognition, working and episodic memory, verbal fluency and the ability to shift attention. Liver biopsies were collected and liver dysfunction was examined with histopathological, biochemical, and gene expression analyses. Linear regression analyses were performed between liver and brain parameters and the influence of body-mass index, diabetes and hypertension was explored. Early stages of liver disease were not associated with cognitive status but with cerebrovascular changes independently of age, sex, BMI, diabetes and hypertension: hepatic fibrosis development was associated with higher spatial coefficient of variation (sCoV) in the nucleus accumbens (NAcc), reflecting greater variations in cerebral perfusion and reduced vascular efficiency. Elevated hepatic levels of free cholesterol and cholesteryl esters were associated with increased WMH, indicating cerebral small vessel disease. RNA-seq and pathway analyses identified associations between sCoV in NAcc and WMH and the expression of hepatic genes involved in inflammation and cellular stress. Additionally, sCoV in NAcc correlated with plasma IL-6 levels suggesting that systemic-low grade inflammation may, at least partly, mediate this relationship. In conclusion, this study demonstrates that specific features of liver dysfunction (e.g. free cholesterol, onset of fibrosis) are associated with subtle cerebrovascular impairments, when changes in cognitive performance are not yet noticeable. These findings highlight the need for future research on therapeutic strategies that normalize metabolic-inflammatory aberrations in the liver to reduce the risk of cognitive decline.
目前尚不清楚肝脏早期的代谢和炎症异常是否与脑结构和认知功能的有害变化相关。这项横断面研究在来自BARICO研究（肥胖症的里恩斯塔特减肥手术和拉德堡德大学医学中心神经影像与认知研究）的70名36至55岁肥胖参与者中，研究了代谢功能障碍相关脂肪性肝病（MASLD）与脑健康之间的假定关联。参与者接受了脑磁共振成像，以研究脑容量和皮质厚度（3T MRI，包括T1加权磁化准备快速梯度回波序列）、脑血流灌注（动脉自旋标记）和白质完整性（扩散加权成像以评估平均骨架化平均扩散率，液体衰减反转恢复序列以检测白质高信号（WMH）的存在）。参与者还进行了神经心理学测试，以评估整体认知、工作和情景记忆、语言流畅性以及注意力转移能力。采集了肝活检样本，并通过组织病理学、生化和基因表达分析检查肝功能障碍。对肝脏和脑参数进行了线性回归分析，并探讨了体重指数、糖尿病和高血压的影响。肝脏疾病的早期阶段与认知状态无关，但与脑血管变化有关，且独立于年龄、性别、体重指数、糖尿病和高血压：肝纤维化的发展与伏隔核（NAcc）中较高的空间变异系数（sCoV）相关，反映了脑灌注的更大变化和血管效率的降低。肝脏中游离胆固醇和胆固醇酯水平升高与WMH增加相关，表明存在脑小血管疾病。RNA测序和通路分析确定了NAcc中的sCoV与WMH以及参与炎症和细胞应激的肝脏基因表达之间的关联。此外，NAcc中的sCoV与血浆IL-6水平相关，表明全身低度炎症可能至少部分介导了这种关系。总之，这项研究表明，当认知表现的变化尚不明显时，肝功能障碍的特定特征（如游离胆固醇、纤维化的发生）与细微的脑血管损伤有关。这些发现凸显了未来对使肝脏代谢炎症异常正常化以降低认知衰退风险的治疗策略进行研究的必要性。
