Increased Extracellular Water in Normal-Appearing White Matter in Patients with Cerebral Small Vessel Disease

Background: Microcirculatory variations have been observed in the normal-appearing white matter (NAWM) of individuals affected by cerebral small vessel disease (CSVD). These variations collectively possess the potential to trigger neuroinflammation and edema, ultimately leading to an elevation in extracellular fluid (ECF). Nevertheless, the specific alterations in ECF within the NAWM of CSVD patients have remained inadequately understood. Methods: We reviewed the clinical and imaging characteristics of a cohort comprising 129 patients diagnosed with CSVD to investigate alterations in the ECF within NAWM. The severity of CSVD was assessed by total CSVD magnetic resonance (MR) score according to the four imaging markers, namely perivascular space, lacunar infarction, white matter hyperintensities and cerebral microbleed. ECF was evaluated by the parameter free water (FW), ranging from 0 to 1 generated from diffusion tensor imaging. Results: Significant differences in NAWM FW were observed in relation to the total CSVD MR score (p < 0.05). Patients with a total CSVD MR score of 0 exhibited significantly lower NAWM free water (FW) values compared to those with a score greater than 0 (p < 0.05). Similarly, patients with a total CSVD MR score of 1 also demonstrated notably lower NAWM FW values than those with a score greater than 1 (p < 0.05). After conducting multivariate regression analysis, age and total CSVD MR score was independently associated with FW in NAWM (p < 0.001). Further, the total CSVD MR score served as a partial mediator in the relationship between age and FW in the NAWM among patients with CSVD. Conclusions: ECF in NAWM is increased in CSVD patients, even during the early course of CSVD.