Abstract
BACKGROUND: White matter hyperintensities (WMHs) represent a cardinal feature of cerebral small vessel disease (CSVD), yet iron dysregulation alterations within these lesions and their relationship to cognitive decline remains poorly understood. OBJECTIVES: To characterize iron dysregulation in WMH using quantitative susceptibility mapping (QSM) and examine their relationship with CSVD severity and cognitive function. DESIGN: Cross-sectional study with longitudinal follow-up component. SETTING: Single-center study at Shandong Provincial Hospital Affiliated with Shandong First Medical University, China. PARTICIPANTS: 299 participants recruited from January 2021 to September 2023, with 71 participants completing longitudinal follow-up (mean interval 20.6 months). Participants were categorized into early CSVD (0 points, n = 171), mild CSVD (1 point, n = 70), and severe CSVD (≥2 points, n = 58) groups based on total burden scoring. INTERVENTION: None (observational study). MEASUREMENTS: 3.0T MRI with quantitative susceptibility mapping and diffusion tensor imaging. Spatial analysis examined susceptibility values in WMH cores and perilesional zones (0-2 mm, 2-4 mm, 4-6 mm). Cognitive assessments included Montreal Cognitive Assessment (MoCA), Symbol Digit Modalities Test (SDMT), and other neuropsychological tests. RESULTS: WMH susceptibility values were significantly lower than normal-appearing white matter (-14.55 vs -7.77 ppb, P < 0.001) with progressive increases correlating with CSVD severity (P < 0.001). Cross-sectionally, higher WMH susceptibility values correlated with lower MoCA scores (r = -0.155, P = 0.045). Longitudinally, WMH susceptibility values predicted decline in information processing speed (SDMT: β = -0.247, P = 0.042). Spatial analysis revealed distinct patterns with perilesional regions showing intermediate susceptibility values. CONCLUSIONS: Iron dysregulation alterations within WMH provide independent information about cognitive risk in CSVD. QSM emerges as a promising biomarker for monitoring cognitive trajectory and may facilitate early identification of patients at risk for cognitive decline.