Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Lena H P Vroegindeweij; Lucia Bossoni; Agnita J W Boon; J H Paul Wilson; Marjolein Bulk; Jacqueline Labra-Muñoz; Martina Huber; Andrew Webb; Louise van der Weerd; Janneke G Langendonk

doi:10.1016/j.nicl.2021.102657

Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Neuroimage Clin. 2021:30:102657. doi: 10.1016/j.nicl.2021.102657. Epub 2021 Apr 3.

Affiliations

¹ Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Porphyria Center Rotterdam, Erasmus University Medical Center, Erasmus MC, Rotterdam, the Netherlands.
² C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: l.bossoni@lumc.nl.
³ Department of Neurology, Erasmus University Medical Center, Erasmus MC, Rotterdam, the Netherlands.
⁴ C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Department of Physics, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333CA Leiden, the Netherlands; Kavli Institute of Nanoscience, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, the Netherlands.
⁶ Department of Physics, Huygens-Kamerlingh Onnes Laboratory, Leiden University, Niels Bohrweg 2, 2333CA Leiden, the Netherlands.

Abstract

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.

Keywords: Aceruloplasminemia; Ferritin; Iron; Magnetometry; Post-mortem MRI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging
Ceruloplasmin / deficiency
Humans
Iron
Iron Metabolism Disorders* / diagnostic imaging
Magnetic Resonance Imaging
Neurodegenerative Diseases* / diagnostic imaging

Substances

Iron
Ceruloplasmin

Supplementary concepts

Familial apoceruloplasmin deficiency