Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Porphyria Center Rotterdam, Erasmus University Medical Center, Erasmus MC, Rotterdam, the Netherlands.
C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
Neuroimage Clin. 2021;30:102657. doi: 10.1016/j.nicl.2021.102657. Epub 2021 Apr 3.
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.
The inhomogeneous transverse relaxation rate (R*) 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.
The brain iron pool in aceruloplasminemia detected in this study consisted of EPR-detectable Fe ions, magnetic Fe embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe 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 Fe ions and maghemite-iron in the temporal cortex in aceruloplasminemia were within the range of those in the control subjects.
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.
铜蓝蛋白缺乏症是一种与大脑内大量铁沉积相关的罕见神经退行性疾病，其分子组成尚不清楚。本研究旨在定量测定铜蓝蛋白缺乏症大脑中的分子铁形式，并阐明其对铁敏感 MRI 指标的影响。
使用 7T MRI 获得的不均匀横向弛豫率（R*）和磁化率，与电子顺磁共振（EPR）和超导量子干涉装置（SQUID）磁强计相结合。对死后铜蓝蛋白缺乏症大脑的基底节、丘脑、红核、齿状核、上颞叶和中颞叶以及白质进行了研究。还纳入了先前从健康对照者颞叶皮质获得的 MRI、EPR 和 SQUID 结果进行比较。
本研究中检测到的铜蓝蛋白缺乏症大脑铁池由 EPR 可检测的 Fe 离子、嵌入铁蛋白核心的磁性 Fe（含铁血黄素铁）和嵌入氧化磁铁矿/磁赤铁矿矿物的磁性 Fe（磁赤铁矿铁）组成。Ferrihydrite-iron 占所有铁的 90%以上，是铁敏感 MRI 对比的主要驱动因素。尽管深部灰质结构中的 Ferrihydrite-iron 比颞叶皮质丰富 3 倍，但与健康情况相比，铜蓝蛋白缺乏症患者颞叶皮质中的 Ferrihydrite-iron 含量已经增加了 6 倍（162µg/g 比 27µg/g），平均而言。铜蓝蛋白缺乏症患者颞叶皮质中的 Fe 离子和磁赤铁矿铁浓度在对照组范围内。
铜蓝蛋白缺乏症中的铁相关神经退行性变主要与 Ferrihydrite-iron 增加有关，Ferrihydrite-iron 是铁敏感 MRI 对比的主要决定因素。
