Perivascular fluid clearance links choroid plexus changes to cognitive performance in cerebral small vessel disease

Choroid plexus (CP) dysfunction may impair cerebrospinal fluid (CSF) turnover and perivascular glymphatic clearance, but whether CP microstructural injury correlates to cerebral small vessel disease (CSVD)-related brain alteration and cognitive performance remains unclear. We investigated whether imaging markers of perivascular fluid transport mediate the associations between CP alterations and CSVD pathology. CP microstructure was assessed by mean apparent propagator (MAP) diffusion imaging and χ-separation susceptibility mapping in 139 CSVD patients and 52 healthy controls. Perivascular clearance measures included the diffusion tensor image-along perivascular space (DTI-ALPS) index, basal ganglia free-water fraction (FW-BG), and perivascular space volume fraction (PVSVF-BG). Compared with controls, CSVD patients showed CP microstructural abnormalities and altered perivascular clearance markers, which was identified by random-forest model as predictors of CSVD severity (OOB-AUC = 0.755, 95%CI: 0.641-0.836). Mediation analysis revealed that imaging markers of perivascular fluid clearance significantly mediated the associations between CP alterations and structural brain injury (average causal mediation effect , ACME=-110.118 to 80.121, FDR-p < 0.05). Notably, PVSVF-BG was the only glymphatic imaging metric mediating the links of both CP volume and susceptibility with cognitive performance (ACME=-142.474 to 67.351, FDR-p < 0.05). These findings indicate that CP microstructural injury are present in mild CSVD with the absence of CP volumetric enlargement, and are associated with CSVD markers and cognitive performance, which are mediated by disrupted perivascular fluid transport, highlighting the CP-glymphatic axis as a candidate pathway for further longitudinal and mechanistic investigation.