Department of Neurology and Center of Clinical Neuroscience, 1st Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, 120 00 Prague, Czech Republic.
Department of Radiology, 1st Faculty of Medicine and General University Hospital in Prague, Charles University in Prague, 120 00 Prague, Czech Republic.
Biomolecules. 2022 May 17;12(5):714. doi: 10.3390/biom12050714.
Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson's disease, Friedreich's disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood-brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
脑铁调节紊乱似乎在衰老和各种神经退行性疾病的发病机制中起作用。铁积累可能带来的不利影响包括活性氧的生成、诱导铁死亡以及加速炎症变化。全脑铁敏感磁共振成像（MRI）技术可用于在体内检查脑铁沉积物的宏观模式，而现代分析方法则可在体外确定单个细胞类型内的金属特异性含量，有时甚至在特定细胞隔室内确定。本综述总结了遗传性和散发性神经退行性疾病中脑铁积累的全脑、细胞和亚细胞模式。我们还提供了这些疾病中脑铁积累的机制、生物标志物和影响的最新信息，重点关注最近的出版物。在帕金森病、弗里德里希共济失调和神经退行性疾病伴脑铁积累组的几种疾病中，存在局灶性铁沉积，通常在具有最明显神经病理学变化的区域。第二类疾病包括多发性硬化症、阿尔茨海默病和肌萎缩侧索硬化症，在苍白球、尾状核和壳核以及特定皮质区域显示铁积累。然而，其他疾病如铜蓝蛋白血症、神经铁蛋白病或威尔逊病则表现为深灰质弥漫性铁积累，其模式与正常衰老时观察到的相似，甚至更广泛。在微观水平上，脑铁沉积物主要存在于变形的小胶质细胞中，铁负荷巨噬细胞和星形胶质细胞也存在于其中，这表明炎症变化和血脑屏障破坏在铁积累中起作用。讨论了神经退行性变中减少铁的策略的选择和潜在益处。需要研究遗传易感性是否在脑 Fe 积累中起作用。如果得到证实，那么在有风险的个体中预防进一步的脑 Fe 摄取可能是预防神经退行性疾病的关键。
