Choroid plexus enlargement contributes to CSVD progression and white matter microstructural deterioration via brain-fluid dysregulation

The choroid plexus (ChP) plays a pivotal role in cerebrospinal fluid (CSF) production, blood-CSF barrier maintenance, and immune surveillance at the brain-periphery interface. While ChP enlargement has been implicated in several neurodegenerative and neuroinflammatory disorders, its role in the pathogenesis of cerebral small vessel disease (CSVD) and frequently cooccurring white matter (WM) microstructural damage has not been systematically investigated, particularly in large-scale, longitudinal, population-based settings. We aimed to determine whether ChP enlargement contributes to CSVD progression, WM microstructural deterioration, and cognitive decline via glymphatic impairment and interstitial fluid accumulation. In a community-based cohort (n = 2,186; mean age 61.3 ± 5.8 years), participants underwent multimodal brain MRI and Montreal Cognitive Assessment (MoCA) at baseline and a median 2.5-year follow-up. Brain-fluid dysregulation was indexed by elevated extracellular free water (FW) and reduced diffusivity along the perivascular spaces (DTI-ALPS). Total CSVD burden, CSVD imaging markers, WM fibre-tract integrity (tissue-specific fractional anisotropy and mean diffusivity), and WM network-level topology were comprehensively assessed. An independent hospital-based cohort (n = 249; mean age 67.2 ± 8.1 years) with comprehensive neuropsychological assessments, was included to serve as an external validation sample and to enable domain-specific analyses of cognitive impairment associated with ChP enlargement. At baseline, larger ChP volume and greater brain-fluid dysregulation (i.e., elevated FW and reduced DTI-ALPS) were consistently associated with higher total CSVD burden, increased white-matter hyperintensity volume, higher numbers of lacunes and cerebral microbleeds, and more pronounced disruption of WM microstructural integrity (at both the WM fibre-tract and network levels), as well as poorer cognitive performance—particularly in executive function and information processing speed. Serial mediation analyses delineated hierarchical cascades: ChP enlargement affected WM microstructural integrity and cognition via elevated FW and reduced DTI-ALPS. Furthermore, in the PRECISE cohort, no significant relationship was observed between baseline ChP volume and longitudinal decline in global cognitive function (∆ MoCA scores). However, higher baseline ChP volume was robustly associated with longitudinal CSVD progression and WM microstructural deterioration over the median 2.5-year follow-up, with increases in FW significantly mediated these associations. These findings support a framework in which ChP enlargement is associated with brain-fluid dysregulation and downstream CSVD pathology and WM microstructural degeneration. Further longitudinal studies incorporating comprehensive neuropsychological batteries are warranted to clarify the role of ChP-related fluid dysregulation in domain-specific cognitive trajectories.