Abstract
BACKGROUND: White matter hyperintensity (WMH) is associated with glymphatic dysfunction. Few studies have focused on the causal effects of the dysfunction of the glymphatic circulation pathways (inflow and outflow pathway) on WMH and cognitive function. METHODS: This study investigated the directional effects between glymphatic circulation, WMH lesions, and cognitive function in older adults based on structural equation models. The lateral ventricle choroid plexus (ChP), the coupling strength between blood oxygen signals in gray matter and cerebrospinal fluid flow, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and meningeal lymphatic vessels (MLVs) were analyzed for quantitative analysis of the glymphatic circulation. RESULTS: Compared to healthy controls, participants with WMH had greater ChP volume, lower DTI-ALPS index, and reduced MLVs function, all associated with worse cognitive performance. Both ChP/LatVent (p = 0.009) and DTI-ALPS (p < 0.001) are significant predictors of WMH volume. Deep WMH (DWMH) partially mediated the relationship between glymphatic function (ChP/LatVent, β = 0.108, p = 0.044; DTI-ALPS, β = 0.122, p = 0.032) and cognition. Structural equation models revealed that glymphatic outflow negatively influenced WMH (β = -0.572, p < 0.001), and WMH had a significantly negative effect on cognitive function (β = -0.705, p = 0.006). CONCLUSIONS: Our results suggest that DWMH plays a mediating role in glymphatic decline and cognitive abnormalities, and that diminished glymphatic circulation affects WMH volume, leading to decreased cognitive function.