Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology

Emerging MRI techniques are progressing towards a means for the quantification of iron concentration or myelin content over the scale of a whole brain at submillimeter resolutions both ex vivo and in vivo. Complementary techniques borrowed from analytical chemistry and solid-state physics can help in the specification and quantification of iron forms in the brain. Multiparametric imaging approaches yielding quantitative information on both iron and myelin content may provide useful biomarkers to assess white matter integrity in clinical studies that use iron chelation therapy for diseases associated with iron deposition. Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration. Although iron is crucial for neuronal functioning, many aspects of cerebral iron biology await clarification. The ability to quantify specific iron forms in the living brain would open new avenues for diagnosis, therapeutic monitoring, and understanding pathogenesis of diseases. A modality that allows assessment of brain tissue composition in vivo, in particular of iron deposits or myelin content on a submillimeter spatial scale, is magnetic resonance imaging (MRI). Multimodal strategies combining MRI with complementary analytical techniques ex vivo have emerged, which may lead to improved specificity. Interdisciplinary collaborations will be key to advance beyond simple correlative analyses in the biological interpretation of MRI data and to gain deeper insights into key factors leading to iron accumulation and/or redistribution associated with neurodegeneration. star-shaped glial cells supporting BBB maintenance, provision of nutrients to neurons, tissue repair, and facilitation of neurotransmission. vascular barrier resulting from tight junctions formed by endothelial cells of cerebral blood vessels; largest interface for blood–brain iron exchange. multicopper ferroxidase existing as membrane-bound and soluble forms (e.g., in plasma and cerebrospinal fluid). vascular tissue in the ventricles producing cerebrospinal fluid in the adult brain. originates from induced currents in the electron cloud within an atom generating weak fields opposing an applied magnetic field. major transmembrane transporter of divalent cations, such as Fe2+, into cells and across endosomal membranes during the transferrin cycle. major iron exporter protein exporting Fe2+ out of cells; exported Fe2+ is oxidized by ferroportin-associated ferroxidases (e.g., hephaestin or ceruloplasmin). membrane-bound ferroxidase that oxidizes Fe2+ exported through ferroportin to Fe3+ that can then be bound to transport proteins. peptide secreted by the liver and possibly other cell types, controlling the amount of iron exported out of cells by ferroportin. exchangeable pool of redox-active iron complexes of low stability within the cell. precession frequency of nuclear spins (or the bulk net magnetization) in a magnetic field. magnetization vector component parallel to the magnetic field. regeneration of longitudinal magnetization at a rate R1 after perturbation of the thermal equilibrium. type of white blood cell that participates in the immune response supporting either a pro- or anti-inflammatory tissue environment that depends on its cellular iron status; major roles include eliminating phagocytic particles, such as cellular debris or bacteria, and foreign substances. physical quantity that describes the magnetization of a material in response to an applied magnetic field; negative for diamagnetic and positive for paramagnetic, ferromagnetic, and ferrimagnetic substances. density of (permanent or induced) magnetic dipole moments in a magnetic material; expresses the extent to which the material is ‘magnetized’. exchange of longitudinal magnetization between water and macromolecules. type of glial cell and the resident macrophages of the brain, thus subserving, in part, similar functions as macrophages. part of iron (essentially low molecular weight one) that is not bound to transferrin. type of neuroglia providing support and insulation to axons in the brain by creating the myelin sheath. originates from spins of unpaired electrons, which tend to align parallel to an applied magnetic field. rotational motion on a cone performed by the axis of a spinning object in response to an external torque. re-establishment of thermal equilibrium after a perturbation. size-dependent form of magnetism typical of nanoparticles; characterized by collective spin dynamics driven by thermal fluctuations. glycoprotein that binds two Fe3+ for transport and delivery to cells; iron-free and iron-loaded forms are apo- and holo-transferrin, respectively. magnetization vector component perpendicular to the magnetic field; generates the MRI signal. leads to MRI signal decay at an effective rate R2∗ = R2 + R2′; fluctuating dipole fields produce irreversible signal loss (rate R2), whereas static field inhomogeneities cause reversible loss (rate R2′).