Differentiating among early-stage parkinsonisms is a challenge in clinical practice. Quantitative MRI can aid the diagnostic process, but studies with singular MRI techniques have had limited success thus far. Our objective is to develop a multi-modal MRI method for this purpose. In this review we describe existing methods and present a dedicated quantitative MRI protocol, a decision model and a study design to validate our approach ahead of a pilot study. We present example imaging data from patients and a healthy control, which resemble related literature.

Aims: Aceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron deposits, of which the molecular composition is unknown. We aimed to quantitatively determine the molecular iron forms in the aceruloplasminemia brain, and to illustrate their influence on iron-sensitive MRI metrics. Methods: The inhomogeneous transverse relaxation rate (R₂*) and magnetic susceptibility obtained from 7 T MRI were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry. The basal ganglia, thalamus, red nucleus, dentate nucleus, superior- and middle temporal gyrus and white matter of a post-mortem aceruloplasminemia brain were studied. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison. Results: The brain iron pool in aceruloplasminemia detected in this study consisted of EPR-detectable Fe³⁺ ions, magnetic Fe³⁺ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe³⁺ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Ferrihydrite-iron represented above 90% of all iron and was the main driver of iron-sensitive MRI contrast. Although deep gray matter structures were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron was already six times more abundant in the temporal cortex of the patient with aceruloplasminemia compared to the healthy situation (162 µg/g vs. 27 µg/g), on average. The concentrations of Fe³⁺ ions and maghemite-iron in the temporal cortex in aceruloplasminemia were within the range of those in the control subjects. Conclusions: Iron-related neurodegeneration in aceruloplasminemia is primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.