Associations of cortical iron accumulation with cognition and cerebral atrophy in Alzheimer’s disease

BACKGROUND: In Alzheimer’s disease (AD), cerebral iron accumulation colocalizes with the pathological proteins amyloid-β (Aβ) and tau. Furthermore, tau-induced cortical thinning is associated with cognitive decline. In this study, quantitative susceptibility mapping (QSM) was used to investigate the whole-brain distribution pattern of cortical iron deposition and its relationships with cognition and cortical thickness in AD. METHODS: This cross-sectional study prospectively recruited 30 participants with AD and 26 age- and sex-matched healthy controls (HCs). All participants underwent QSM and T(1)-weighted examinations on a 3.0T MRI scanner. Global cognition was assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Whole-brain cross-sectional QSM analysis and whole-brain QSM regression analyses against the MMSE and MoCA scores were performed. Surface-based morphometry analysis was also performed. Subsequently, in regions with significant atrophy, magnetic susceptibility was compared between the AD and HC groups, and the association between magnetic susceptibility and cortical thickness was assessed. RESULTS: Whole-brain QSM cross-sectional analysis in the AD group demonstrated widespread increased susceptibility across the cortical ribbon, asymmetrically covering the left hemisphere cerebral cortex, caudate nucleus, putamen, and partial cerebellar cortex. Whole-brain QSM regression analyses in the AD group showed that increased susceptibility covaried with lower MMSE and MoCA scores, and was predominantly located in the right parietal cortex and lateral occipital cortex. In the AD group, cortical thickness was reduced in the left superior temporal gyrus, right frontal pole, fusiform gyus, and pars opercularis, and there were increases in susceptibility in the right frontal pole (AD: mean ± SD 0.034±0.007 ppm, 95% CI: 0.032–0.037 ppm; HC: 0.030±0.005 ppm, 95% CI: 0.028–0.032 ppm; P=0.016) and pars opercularis (AD: 0.020±0.003 ppm, 95% CI: 0.018–0.021 ppm; HC: 0.017±0.002 ppm, 95% CI: 0.017–0.018 ppm; P=0.002). Susceptibility was negatively correlated with cortical thickness in the right pars opercularis in the entire cohort (r=–0.521, P<0.001) and AD group (r=–0.510, P=0.005). CONCLUSIONS: Widespread cortical iron, as measured by QSM, accumulated in AD and iron deposition was associated with poor cognitive performance. Increased iron content was also associated with brain atrophy. Our study suggests QSM may be a useful imaging biomarker for monitoring the neurodegenerative progression of AD.