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.

Department of Clinical Physiology St Goran Hospital 112 81 Stockholm Sweden

Department of Environmental Health Division of Climate and Health Norwegian Institute of Public Health P O Box 222 Skøyen 0213 Oslo Norway

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Prague Charles University Prague 120 00 Prague Czech Republic

Department of Radiology 1st Faculty of Medicine and General University Hospital Prague Charles University Prague 120 00 Prague Czech Republic

Faculty of Health and Social Sciences Inland Norway University of Applied Sciences P O Box 400 2418 Elverum Norway

Institute of Environmental Medicine Karolinska Institutet 171 77 Stockholm Sweden

Research Department Innlandet Hospital Trust P O Box 104 2381 Brumunddal Norway

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