More then simply iron: Macro- to microscopic cellular iron distribution in the brain determines MR contrast

Myelin and iron are the major source of MR contrast in the brain. Iron dominates R2*, R2 and QSM in the cortex as well as in subcortical areas and contributes to white matter contrast. To exploit this contrast for cortical parcellation, myeloarchitecture mapping, or iron quantification, significant theoretical and experimental efforts were devoted to the understanding of iron-induced contrast. However, the impact of the cellular and subcellular iron distribution is not well understood. Frequently, it is described by a simple linear dependence of the MRI contrast parameters on iron concentration, largely disregarding the inhomogeneous distribution of iron in the brain. A major reason for this simplification is a lack of quantitative knowledge on the cellular iron distribution. Moreover, the interplay between the microscopic iron distribution and diffusion in creating MR contrast in static de-phasing, motional narrowing or intermediate regime is not fully understood. We set out to address this lack in knowledge and modelling by combining state of the art quantitative 7T MRI with cutting-edge quantitative iron and myelin mapping on post mortem brain samples. Quantitative R2*, R2, R1 and QSM maps were obtained for the human cortex, the subcortical and the deep white matter as well as for brain nuclei before and after de-ironing. Laser Ablation Inductively Coupled Plasma Mass Spectroscopic Imaging (LA ICP MSI) yielded quantitative iron maps with a mesoscopic resolution of 60x120μm. Proton Induced X-ray Emission (PIXE) provided quantitative iron maps with a cellular resolution down to 1μm. MSI and PIXE demonstrated the inhomogenous distribution of iron in both grey and white matter at different spatial scales. In grey matter iron rich fibers, and small (1-3μm) micro-, astro- and oligodendroglia contained most of the iron and were sparsely distributed. In superficial and deep white matter, however, oligodendrocytes somas with the sizes of 5±1.5μm (distance between cells of 20±5μm) and iron rich fibers contained most of the iron. In addition, patches of enhanced iron concentration around small vessels with a typical size of 100-200μm contribute to up to 20% of R2* and QSM and their orientation dependence in white matter. A different contrast mechanism prevailed in brain nuclei where densely packed 20μm large iron loaded neurons dominated the MR contrast. These results provide an important basis for understanding the iron induced MR-contrast and its microstructural underpinnings. Based on these measured microscopic iron distributions and a Gaussian diffusion model we are now in the process of simulating the MR contrast mechanisms in different tissue types