Beyond iron concentration: iron aggregation shapes quantitative MRI in the human brain

Aceruloplasminemia (ACP) is a rare neurodegenerative disorder characterized by extreme cerebral iron overload and a shift towards larger iron aggregates, providing a unique possibility to study how iron aggregation shapes MRI contrast in vivo. We introduce a clinically feasible, multi-parametric quantitative MRI (qMRI) framework that combines quantitative susceptibility mapping (QSM), [Formula], and R2 to disentangle changes in total iron concentration from alterations in iron aggregation and its spatial organization at the cellular scale. Our biophysical model links the microstructure sensitive [Formula] ratio and the slope of the susceptibility-relaxation relationship (iron) to iron aggregation size and distribution. In a 3T qMRI study of three patients with ACP and three matched controls, we observe a marked increase in [Formula] and a pronounced increase of the [Formula]-QSM slope (iron: controls 154.09 {+/-} 52.89 s-1ppm-1; patients 296.68 {+/-} 57.18 s-1ppm-1; p = 0.016), consistent with enhanced iron aggregation and altered spatial organization. Model-based decomposition of transverse relaxation indicates that up to approximately 40% of the observed R2* elevation in ACP is attributable to changes in iron distribution beyond increased iron concentration alone. These findings establish a robust, translational qMRI approach for quantitative in vivo assessment of iron aggregation, revealing microstructural drivers of iron-related neurodegeneration that extend beyond bulk iron load.