White matter hyperintensity iron overload mediates glymphatic system dysfunction and cognitive impairment in cerebral small vessel disease

Motivation: The mechanism underlying the relationship between glymphatic system dysfunction and cognitive impairment in cerebral small vessel disease (CSVD) remains unclarified. Goal(s): This study aimed to explore the role white matter hyperintensity (WMH) iron burden played in the pathogenesis of CSVD. Approach: WMH iron burden was calculated using iterAtive magnetic suscePtibility sources sepARaTion QSM (APART-QSM), a sub-voxel quantitative method. Glymphatic system function was measured by DTI analysis ALong the Perivascular Space (DTI-ALPS) index. The relationships between WMH iron burden, DTI-ALPS index, and cognitive scores were examined through correlation and mediation analyses. Results: WMH iron burden mediated DTI-ALPS index and cognitive score in CSVD. Impact: Noninvasively, this study found WMH iron overload as a potential mediator in the relationship between glymphatic system dysfunction and cognitive impairment in CSVD, offering new insights for elucidating the pathological mechanisms underneath.