Free water in white matter links focal hemodynamic compromise to cognitive impairment in asymptomatic extracranial carotid artery stenosis

To investigate the multivariate associations among focal hemodynamic impairment, cerebral interstitial fluid accumulation (measured as free water in white matter, FW-WM), diffuse white matter injury, and cognitive decline in patients with asymptomatic unilateral severe extracranial internal carotid artery stenosis (ICAS). This study included 40 patients with asymptomatic unilateral severe extracranial ICAS and 40 matched healthy controls (HCs). All participants underwent multimodal MRI, including diffusion tensor imaging for FW-WM and FW-corrected fractional anisotropy (fwcFA), 3D-T2 FLAIR for white matter hyperintensities (WMH) volume, and arterial spin labeling for cerebral blood flow (CBF). CBF was quantified at two post-labeling delays (PLDs: 1500 ms and 2500 ms) in grey matter (GM) and, at 2500 ms, additionally in white matter (WM) of the anterior, middle, and posterior cerebral artery (ACA, MCA, PCA) territories. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) within the patient group. Compared to HCs, patients exhibited significantly elevated global FW-WM (0.20 ± 0.03 vs. 0.18 ± 0.02, p < 0.001), reduced fwcFA (0.45 ± 0.014 vs. 0.46 ± 0.013, p = 0.017), greater WMH volume (median: 4.41 vs. 2.43 cm³, p = 0.003), and more pronounced lateralized CBF reductions in the ACA and MCA territories (all p < 0.05), indicating hemodynamic impairment. Within-patient analyses revealed a dual pathology: focal ipsilateral changes (elevated FW-WM and reduced CBF) and diffuse bilateral changes (symmetric WMH and FA reduction). After controlling for covariates, ipsilateral FW-WM correlated negatively with the lateralization index of CBF in the ACA GM (LI-CBF-ACA-GM) at PLD 1500ms and 2500ms (r = -0.464, p = 0.005 and r = -0.416, p = 0.013, respectively). Global FW-WM correlated positively with total WMH volume (r = 0.344, p = 0.043) and strongly negatively with fwcFA (r = -0.599, p < 0.001). Multivariable linear regression confirmed that FW-WM was independently associated with both ipsilateral hemodynamic impairment and global white matter injury, adjusting for age, sex, hypertension, diabetes, and homocysteine. Crucially, higher global FW-WM was associated with worse MoCA scores (r = -0.435, p = 0.007), and this association remained significant after separately adjusting for either WMH volume (partial r = -0.361, p = 0.030) or LI-CBF-ACA-GM (partial r = -0.363, p = 0.029). In asymptomatic extracranial ICAS, elevated FW‑WM integrates dual pathologies of focal hemodynamic impairment and diffuse white matter injury. Its independent association with cognitive decline positions FW-WM not only as a pivotal mechanistic link between hemodynamic compromise and clinical impairment, but also as a promising imaging biomarker. Prospective studies are warranted to validate its utility in stratifying the risk of progressive white matter injury and cognitive decline in this population.