White matter hyperintensities (WMHs) are one of the hallmarks of cerebral small vessel disease (CSVD), but the pathological mechanisms underlying WMHs remain unclear. Recent studies suggest that extracellular fluid (ECF) is increased in brain regions with WMHs. It has been hypothesized that ECF accumulation may have detrimental effects on white matter microstructure. To test this hypothesis, we used cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a unique CSVD model to investigate the relationships between ECF and fiber microstructural changes in WMHs. Thirty-eight CADASIL patients underwent 3.0 T MRI with multi-model sequences. Parameters of free water (FW) and apparent fiber density (AFD) obtained from diffusion-weighted imaging (b = 0 and 1000 s/mm2) were respectively used to quantify the ECF and fiber density. WMHs were split into four subregions with four levels of FW using quartiles (FWq1 to FWq4) for each participant. We analyzed the relationships between FW and AFD in each subregion of WMHs. Additionally, we tested whether FW of WMHs were associated with other accompanied CSVD imaging markers including lacunes and microbleeds. We found an inverse correlation between FW and AFD in WMHs. Subregions of WMHs with high-level of FW (FWq3 and FWq4) were accompanied with decreased AFD and with changes in FW-corrected diffusion tensor imaging parameters. Furthermore, FW was also independently associated with lacunes and microbleeds. Our study demonstrated that increased ECF was associated with WM degeneration and the occurrence of lacunes and microbleeds, providing important new insights into the role of ECF in CADASIL pathology. Improving ECF drainage might become a therapeutic strategy in future.

中文翻译：

---

细胞外液增加与 CADASIL 白质纤维变性有关：来自扩散磁共振成像的体内证据

白质高信号 (WMHs) 是脑小血管病 (CSVD) 的标志之一，但 WMHs 的病理机制仍不清楚。最近的研究表明，具有 WMH 的大脑区域的细胞外液 (ECF) 增加。据推测，ECF 积累可能对白质微观结构产生不利影响。为了验证这一假设，我们使用伴有皮质下梗死和白质脑病的常染色体显性脑动脉病 (CADASIL) 作为独特的 CSVD 模型来研究 ECF 与 WMH 中纤维微观结构变化之间的关系。38 名 CADASIL 患者接受了具有多模型序列的 3.0 T MRI。从扩散加权成像（b = 0 和 1000 s/mm2）获得的自由水 (FW) 和表观纤维密度 (AFD) 的参数分别用于量化 ECF 和纤维密度。WMH 被分成四个子区域，每个参与者使用四分位数（FWq1 到 FWq4）四个级别的 FW。我们分析了 WMHs 的每个子区域中 FW 和 AFD 之间的关系。此外，我们测试了 WMH 的 FW 是否与其他伴随的 CSVD 成像标志物相关，包括腔隙和微出血。我们发现 WMH 中 FW 和 AFD 之间存在负相关。具有高水平 FW（FWq3 和 FWq4）的 WMH 子区域伴随着 AFD 的减少和 FW 校正的弥散张量成像参数的变化。此外，FW 还与腔隙和微出血独立相关。我们的研究表明，ECF 增加与 WM 变性以及腔隙和微出血的发生有关，为 ECF 在 CADASIL 病理学中的作用提供了重要的新见解。改善 ECF 引流可能成为未来的治疗策略。