Fifty Shades of Grey Matter: This is My Brain on Aging


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By contrast, a more general involvement of deep grey matter nuclei and grey matter in general with respect to iron accumulation is seen in aceruloplasminaemia, but without evidence of cystic processes. It is the most common of the polyglutamine diseases, affecting about one in 10 individuals worldwide. In embryonic stem cells, huntingtin is iron-regulated and also involved in iron homoeostasis regulation.

Restless legs syndrome is characterised by reduced iron function. Autopsy and MRI investigations show decreased iron concentrations in the substantia nigra of patients with restless leg syndrome that are associated with disease severity. Development of high-field 7 T and above MRI has great relevance to the study of brain iron.

High-field MRI has great potential for the study of subtle variations in iron at low spatial resolution, even outside the regions of deep grey matter nuclei with high iron concentrations.

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For example, in a study of healthy brains substantial iron concentration variations were shown in the different cortical layers figure 3. In-vivo and post-mortem investigations suggest focal iron accumulation in the white matter in multiple sclerosis , , and focal iron accumulation in the cortex in amyotrophic lateral sclerosis co-localise with microglia appendix.


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For example, the sensitivity of MRI to tissue myelin content and integrity , might help to establish the temporal relation between iron accumulation and the demyelinating process in multiple sclerosis. A Laminar variations shown in luxol fast blue myelin stain. Laminar patterns seem specific to functional areas V1 and V2.

The dashed line indicates calcarine sulcus. Solid arrows, open arrows, and arrowheads show areas of increased iron in central and deep layers, and subcortical white matter. Reproduced from Fukunaga and colleagues with permission of Proceedings of the National Academy of Sciences. The potential therapeutic use of iron chelators to remove excess iron from specific brain regions affected by neurodegenerative diseases has received much attention.

To be effective, an iron chelator should be able to penetrate both cellular membranes and the blood—brain barrier, target the region of iron accumulation without depleting transferrin-bound iron from the plasma, and be able to remove chelatable iron from the site of accumulation or to transfer it to other biological proteins, such as circulating transferrin. Furthermore, whether iron chelators can remove iron from conjugated iron containing proteins and molecules, such as neuromelanin, is unknown; the chelators in clinical use were developed to remove iron from ferritin and haemosiderin in grossly iron overloaded tissues, such as the liver and spleen, and to a lesser extent the heart.

MRI is a promising technique to assess the efficacy of a treatment, although the quantitative accuracy of MRI might be dependent on the type and molecular distribution eg, cluster size and oxidation state of iron. Genetic with transgenic expression of ferritin or pharmacological by clioquinol iron chelation resulted in the reduction of reactive iron protecting mice from the toxic effects derived from 1-methylphenyl-1,2,3,6-tetrahydropyridine.

Three of the 40 patients in the first study developed neutropenia or agranulocytosis, which were resolved rapidly with cessation of deferiprone. Despite such positive results, no other clinical studies of deferrioxamine have been reported. PBT2 binds excesses of copper and zinc and possibly iron in the brain, thereby diminishing the amount of amyloid plaque formation and relocating these metal ions to depleted cellular and neuronal compartments.

This reduction was associated with neurological improvements in manipulative dexterity, speech fluency, and a reduction in neuropathy and ataxia gait, particularly in the youngest patients. A reduction in iron content was seen after 2 months of treatment and the effect was proportional to the concentration of initial accumulated iron. Boddaert and colleagues suggested that the form of iron chelated was a labile iron pool, with iron possibly being bound to enzymes, such as hydroxylases, and to ferritin.

MRI values in the dentate nuclei of participants showed a significant reduction of iron that was associated with significant recovery of kinetic functions, although gait and posture scores worsened. Subcutaneous infusion of deferoxamine was reported to be effective in patients with aceruloplasminaemia. The oral chelator deferasirox was effective in a year-old man to treat left-side choreoathetosis and an unsteady gait. Chelation therapy has been reported to provide improvements, notably with deferiprone, and particularly for other neurodegeneration with brain iron accumulation diseases, but no improvement was seen in two patients with neuroferritinopathy.

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How the different brain regions maintain iron concentrations under normal circumstances, and the changes that occur with ageing and after an inflammatory insult, are not known. In peripheral iron-loading diseases, such as thalassaemias and haemochromatosis, no evidence has been reported of an increased incidence of neurodegeneration, nor of elevated concentrations of brain iron, despite the massive iron deposition in parenchymal tissues. We therefore suggest that the brain represents a privileged body compartment, which in normal circumstances does not respond to peripheral variations in iron status.

Neurodegenerative diseases might be caused by changes in brain iron from compartments where iron is quiescent to other parts of the brain where iron is neurotoxic. The future challenge is to establish the mechanisms involved in brain iron changes on a disease by disease basis. We expect MRI to have an important role, possibly in a quantitative or a semi-quantitative manner. If brain iron patterns are characteristic of disease or disease stage, this might have a great effect on a diagnosis.

Although total iron measures might be dominated by biologically inert forms sequestered in ferritin, neuromelanin, and other molecules, they might be predictive for bioactive iron species and, as such, have relevance for the study of disease. High-field MRI developments might advance the ability to map distributions of iron quantitatively, increasing knowledge of the pathogenesis of neurological disorders.

Unfortunately, it is difficult to relate tissue iron concentrations to those in specific cell types, for which we presently rely on scarce information from studies done many years ago. Despite increases in the resolution of MRI images of iron distribution, MRI cannot measure concentrations of specific iron molecules in particular cells. Processes involved with age-related and disease-related accumulation of iron and iron-induced inflammation in specific brain regions and cells are poorly understood. Future research should focus on the accurate mapping of iron in healthy brains, at different ages, and in neurodegenerative disorders to begin to interpret regional variations in brain iron.

Because much of our present knowledge about iron homoeostasis relies on studies on young healthy rodents whose iron pathways have some important differences to elderly human brains , valuable information might be gleaned from experiments on human induced pluripotent stem cells, primates, and in ex-vivo human brain tissues. We thank Francesca A Cupaioli for her assistance in bibliographic research.

See Online for appendix. National Center for Biotechnology Information , U. Author manuscript; available in PMC Nov 6. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Lancet Neurol. See other articles in PMC that cite the published article. Associated Data Supplementary Materials Supplementary.

Abstract In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Introduction Iron is involved in many fundamental biological processes in the brain including oxygen transportation, DNA synthesis, mitochondrial respiration, myelin synthesis, and neurotransmitter synthesis and metabolism. Regulation of cellular iron Peripheral iron uptake Iron released as ferrous iron from specific cells ie, macrophages, hepatocytes via ferroportin, is oxidised by ferroxidase ceruloplasmin and binds to circulating apo-transferrin panel ; in enterocytes, hephaestin, a ceruloplasmin analogue, might have this role.

Brain iron uptake Figure 1 summarises present understanding of iron homoeostasis in the brain. Open in a separate window. Brain iron metabolism Iron enters the endothelial cells of the blood—brain barrier as a low molecular weight complex, or via transferrin receptor-1 mediated endocytosis of transferrin, or independently as non-transferrin-bound iron. Iron changes in brain ageing Increased concentrations of total iron with ageing might be caused by several factors that include increased blood—brain barrier permeability, inflammation, redistribution of iron within the brain, and changes in iron homoeostasis.

Neurodegenerative mechanisms involving iron Iron accumulation in brain cells needs to be tightly regulated to prevent toxic effects. Multiple sclerosis Increased iron concentrations occur in specific brain regions in multiple sclerosis, most prominently in the deep grey matter structures, often with bilateral presentation. Aceruloplasminaemia and neuroferritonopathy The class of diseases known as neurodegeneration with brain iron accumulation encompasses a wide range of genetically distinct adult and paediatric neurological diseases.

Restless legs syndrome Restless legs syndrome is characterised by reduced iron function. MRI detection of fine-scale spatial variation in iron content in healthy brain tissue A Laminar variations shown in luxol fast blue myelin stain. Iron chelation as a potential therapy Overview The potential therapeutic use of iron chelators to remove excess iron from specific brain regions affected by neurodegenerative diseases has received much attention.

Aceruloplasminaemia and neuroferritonopathy Subcutaneous infusion of deferoxamine was reported to be effective in patients with aceruloplasminaemia. Conclusions and future directions How the different brain regions maintain iron concentrations under normal circumstances, and the changes that occur with ageing and after an inflammatory insult, are not known. Supplementary Material Supplementary Click here to view. Ceruloplasmin can exist as a soluble form in plasma and other fluids or as a membrane bound form the glycophosphatidylinositol-anchored form of ceruloplasmin, which is highly expressed at the end-foot of astrocytes in the mammalian CNS.

Divalent metal ion transporter 1 DMT1 The major transmembrane transporter of ferrous iron and other divalent metal cations into cells eg, enterocytes. DMT1 has an important role in the efflux of ferrous iron from endosomes during the transferrin cycle. Ferritin The major iron storage protein in which iron is stored in as a soluble, non-reactive, or bio-available form. In mammals, ferritin is a heteropolymer composed of two types of subunits, ferritin heavy chain and ferritin light chain; the ratio of heavy to light chain is tissue specific.

The heavy chain shows ferroxidase activity, and converts ferrous iron to ferric iron before being stored inside the iron core, whereas the light chains have no ferroxidase activity but play an important part in the nucleation of the iron core inside the protein. Ferroportin The major exporter of iron out of some cells.

Iron is exported in the form of ferrous iron therefore the catalytic activity of ferroxidase is needed. The associated ferroxidase oxidises exported ferrous iron into ferric iron and this function is mainly accomplished by hephaestin in the gut or by ceruloplasmin. Hepcidin A small peptide secreted mainly by the liver and possibly other cell types, such as glial cells; secretion is dependent on the iron loading and inflammatory status, and controls the quantity of iron translocated by ferroportin out of cells.

When hepcidin binds to ferroportin, this induces internalisation followed by degradation of the complex in lysosomes. Hephaestin A membrane bound ceruloplasmin analogue that participates in iron export from enterocytes. Hephaestin acts as a multicopper ferroxidase, oxidising ferrous iron exported from enterocytes through ferroportin to ferric iron that can then be rapidly bound to circulating transferrin or other iron carrier proteins.


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  7. Neuromelanin A complex polymeric molecule present in the human CNS, which is located in organelles surrounded by a double membrane. Neuromelanin pigment is able to accumulate different metals, mainly iron. Neuromelanin seems to be the most effective system for scavenging iron, which results in a long-term immobilisation of iron inside neurons. Pigmented neurons of the substantia nigra and locus coeruleus have the highest levels of neuromelanin in the brain. Transferrin A high-affinity iron—binding protein apo-transferrin or iron-free transferrin that binds two ferric iron atoms, holo-transferrin or diferric transferrin, and is present in plasma, transports iron in serum, lymphatic system, and CSF, and delivers iron to cells via the transferrin cycle.

    Transferrin receptor TFR TFR1, expressed on the membrane of most cells, is the main receptor for transferrin and selectively binds diferric transferrin to internalise it through receptor-mediated endocytosis transferrin cycle. TFR2, the function of which is not well understood but is distinct from TFR1, is an iron sensor in the regulation of hepcidin expression. Labile iron pool Chelatable and redox-active iron in complexes of low stability.

    Footnotes See Online for appendix Contributors All authors equally contributed to all parts of the Review. All authors revised the manuscript and approved the final version.

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    Inorganic biochemistry of iron metabolism from molecular mechanisms to clinical consequences. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Iron, Neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging.

    Mechanisms of brain iron transport: Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Moos T, Morgan EH.

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    Transferrin and transferrin receptor function in brain barrier systems. Iron trafficking inside the brain. Ke Y, Qian ZM. Functional roles of transferrin in the brain. Jeong SY, David S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. The pivotal role of astrocytes in the metabolism of iron in the brain.

    Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Transferrin receptor on endothelium of brain capillaries. The role of iron in neurodegeneration. Milardi D, Rizzarelli E, editors. Heterogenous distribution of ferroportin-containing neurons in mouse brain.

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    Developmental iron uptake and axonal transport in the retina of the rat. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Astrocyte-endothelial interactions at the blood-brain barrier. Xu J, Ling EA. Studies of the ultrastructure and permeability of the blood-brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers.

    Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. Relationship of iron to oligodendrocytes and myelination. J Wiley and Son; Cellular management of iron in the brain. The IL and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells.

    Microglia in the aging brain. J Neuropathol Exp Neurol. Iron accumulation during cellular senescence. Ann N Y Acad Sci. Pathogenic implications of iron accumulation in multiple sclerosis. Impaired iron status in aging research. Int J Mol Sci. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. Iron levels in the human brain: J Trace Elem Med Biol.

    Brain trace elements and aging. Interaction of Neuromelanin and iron in substantia nigra and other areas of human brain. The determination of iron and other metals by INAA in cortex, cerebellum and putamen of human brain and in their neuromelanins. J Radioanal Nucl Chem.

    Brain ferritin iron may influence age- and gender-related risks of neurodegeneration. Age-related iron deposition in the basal ganglia: Gender and iron genes may modify associations between brain iron and memory in healthy aging. MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping. Neuromelanin and iron in human locus coeruleus and substantia nigra during aging: New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals.

    Heme oxygenase-1 and neurodegeneration: Oxidative DNA damage and nucleotide excision repair. Protein carbonylation in human diseases. Mitochondrial iron metabolism and its role in neurodegeneration. Catechol oxidation by peroxidase-positive astrocytes in primary culture: Sulzer D, Zecca L. Dopamine-dependent iron toxicity in cells derived from rat hypothalamus.

    Iron-mediated bioactivation of 1-methylphenyl-1,2,3,6-tetrahydropyridine MPTP in glial cultures. Metallobiology of 1-methylphenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Iron III induces aggregation of hyperphosphorylated tau and its reduction to iron II reverses the aggregation: Liu Y, Connor JR. Iron and ER stress in neurodegenerative disease. Mitochondria, oxidative stress and cell death.

    Free Radic Biol Med. Altamura S, Muckenthaler MU. Iron toxicity in diseases of aging: Implication of the proprotein convertases in iron homeostasis: Silvestri L, Camaschella C. J Cell Mol Med. A synthetic peptide with the putative iron binding motif of amyloid precursor protein APP does not catalytically oxidize iron.

    The amyloid precursor protein APP does not have a ferroxidase site in its E2 domain. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Magnetic resonance imaging of brain iron. Imaging iron stores in the brain using magnetic resonance imaging. High-field MRI of single histological slices using an inductively coupled, self-resonant microcoil: Role of brain iron accumulation in cognitive dysfunction: Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.

    The scientists looked specifically at the association between age and gray matter. People in both groups showed a loss of gray matter as they aged. Florian Kurth, a co-author of the study and postdoctoral fellow at the UCLA Brain Mapping Center, said the researchers were surprised by the magnitude of the difference. As baby boomers have aged and the elderly population has grown, the incidence of cognitive decline and dementia has increased substantially as the brain ages.

    Each group in the study was made up of 28 men and 22 women ranging in age from 24 to Those who meditated had been doing so for four to 46 years, with an average of 20 years. Although the researchers found a negative correlation between gray matter and age in both groups of people — suggesting a loss of brain tissue with increasing age — they also found that large parts of the gray matter in the brains of those who meditated seemed to be better preserved, Kurth said. The researchers cautioned that they cannot draw a direct, causal connection between meditation and preserving gray matter in the brain.

    Too many other factors may come into play, including lifestyle choices, personality traits, and genetic brain differences.

    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging
    Fifty Shades of Grey Matter: This is My Brain on Aging Fifty Shades of Grey Matter: This is My Brain on Aging

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