Assessing glymphatic role in the association between choroid plexus enlargement and white matter lesions load: The uncertain path through diffusion tensor imaging along the perivascular space (DTI-ALPS)

Abstract

Background The choroid plexus (CP) is involved in cerebrospinal fluid production, immune surveillance, and brain fluid homeostasis. CP enlargement has been linked to neuroinflammation, glymphatic dysfunction, and white matter lesion (WML) burden, but the mechanisms underlying these associations remain uncertain . Objective To investigate the relationships among CP volume, glymphatic function estimated using diffusion tensor imaging along the perivascular space (DTI-ALPS), WML burden, and global cognitive performance in individuals with suspected neurodegenerative conditions, and to assess whether DTI-ALPS mediates the association between CP enlargement and white matter damage. Methods We retrospectively analyzed 104 participants, including 63 individuals with neurodegenerative conditions and 41 without neurodegeneration, who underwent multimodal MRI with 3D-T1-weighted, 3D-FLAIR, and diffusion-weighted sequences. CP volume was segmented using ASCHOPLEX and normalized to total intracranial volume. DTI-ALPS indices were derived from diffusion imaging, WML burden was quantified by automated segmentation, and global cognition was assessed using the Mini-Mental State Examination. Associations were tested using linear and quantile regression models. Mediation analysis evaluated indirect effects through DTI-ALPS. Results Greater CP volume was associated with lower DTI-ALPS values and higher WML burden. DTI-ALPS partially mediated the relationship between CP volume and WML burden, although the magnitude of mediation was modest. No significant mediation effect was observed for global cognitive performance. DTI-ALPS also showed strong associations with white matter integrity metrics, suggesting possible sensitivity to non-glymphatic microstructural changes. Conclusions CP enlargement is associated with reduced DTI-ALPS and greater WML burden, but the contribution of glymphatic impairment remains uncertain. Alternative mechanisms, including neuroinflammation, blood–brain barrier dysfunction, and white matter microstructural damage, may contribute to these findings.