Free water–mediated associations among choroid plexus enlargement, white matter lesions, and cognitive performance in type 2 diabetes mellitus

Background Recent studies indicate choroid plexus (CP) enlargement and glymphatic-related brain fluid changes in type 2 diabetes mellitus (T2DM), but how these alterations relate to white matter hyperintensities (WMH) and cognitive impairment in T2DM remains unclear. Methods This study comprised a total of 104 patients diagnosed with T2DM along with 56 healthy controls, who underwent brain MRI and neuropsychological assessment. CP volume, free water (FW) fraction, perivascular space (PVS) volume, and WMH volumes were quantified. Within the T2DM group, the relationship among imaging markers, WMH burden and cognitive performance was examined using multivariable linear regression and mediation analyses. Results The T2DM patients exhibited lower Symbol Digit Modalities Test (SDMT) scores and larger CP volume, FW fraction, PVS volume, and periventricular WMH (PWMH) volume than controls (all P < 0.05). In T2DM patients, CP volume (β = 0.20, P = 0.01) and FW fraction (β = 0.29, P < 0.01) were independently associated with PWMH, while FW fraction (β = −0.31, P < 0.01) and PWMH (β = −0.32, P = 0.01) were independently linked to SDMT. Mediation analyses showed significant statistical indirect effects through FW in the CP–PWMH association (β = 0.07, 95% CI 0.01 to 0.13), through PWMH in the FW–SDMT association (β = −0.09, 95% CI −0.18 to −0.02), and through FW in the CP–SDMT association (β = −0.07, 95% CI −0.15 to −0.02). Conclusions FW-related brain fluid alterations are associated with CP enlargement, periventricular white matter lesion burden, and processing speed performance in T2DM.