Abstract
AimsAceruloplasminemia 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. MethodsThe 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. ResultsThe 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. ConclusionsIron-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.
Highlights
Aceruloplasminemia (OMIM #604290) is a severe adult-onset form of Neurodegeneration with Brain Iron Accumulation (NBIA), caused by homozygous or compound heterozygous mutations in the ceruloplasmin (CP) gene
We present a quantitative overview of Fe3+ ions detected by Electron Paramagnetic Resonance (EPR), and magnetic Fe3+ embedded in ferritin cores or hemosiderin and oxidized magnetite/maghemite minerals, as detected by magnetometry
Two Isothermal Remanent Magnetization (IRM) curves were acquired: one at 5 K, which can report on ferrihydrite, the mineral found in the core of ferritin proteins and hemosiderin aggregates; and a second at 100 K, which saturated around 250 mT, indicative of magnetite or its oxidation product, maghemite
Summary
Aceruloplasminemia (OMIM #604290) is a severe adult-onset form of Neurodegeneration with Brain Iron Accumulation (NBIA), caused by homozygous or compound heterozygous mutations in the ceruloplasmin (CP) gene. QSM, on the other hand, has the potential to differentiate between myelin and iron, based on their opposite effects on tissue susceptibility (Gong et al, 2019), and seems less affected by the cellular localization of iron (Colgan et al, 2020) Both iron-sensitive MRI techniques have been used for the quantitative assessment of iron in aceruloplasminemia brain tissue (Pan et al, 2011; Zhou et al, 2020), but only provided indirect information on the total iron concentrations and not their specification (Bulk et al, 2018). Since MRI is the major imaging modality capable of studying brain iron accumulation in vivo, further specification of the molecular basis of iron-sensitive MRI contrast is key to gain more in-depth pathophysiological insights into different clinical stages of iron-related neurodegeneration
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