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      Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease

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          Abstract

          The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.

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          Most cited references 108

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          Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson's disease.

          We carried out an investigation to identify neuromelanin-containing noradrenergic and dopaminergic neurons in the locus ceruleus and substantia nigra pars compacta of healthy volunteers and patients with Parkinson's disease using a newly developed magnetic resonance imaging technique that can demonstrate neuromelanin-related contrast. The high-resolution neuromelanin images obtained by a 3-T scanner revealed high signal areas in the brain stem and these corresponded well with the location of the locus ceruleus and substantia nigra pars compacta in gross specimens. In Parkinson's disease patients, the signal intensity in the locus ceruleus and substantia nigra pars compacta was greatly reduced, suggesting depletion of neuromelanin-containing neurons. We conclude that neuromelanin magnetic resonance imaging can be used for direct visualization of the locus ceruleus and substantia nigra pars compacta, and may help in detecting pathological changes in Parkinson's disease and related disorders.
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            A New Method of Measuring Nuclear Magnetic Moment

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              MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration

              Subsets of rodent neurons are reported to express major histocompatibilty complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression, and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell derived dopamine (DA) neurons. Catecholamine murine cultured neurons are more responsive to induction of MHC-I by gamma-interferon than other neuronal populations. Neuronal MHC-I is also induced by factors released from microglia activated by neuromelanin or alpha-synuclein, or high cytosolic DA and/or oxidative stress. DA neurons internalize foreign ovalbumin and display antigen derived from this protein by MHC-I, which triggers DA neuronal death in the presence of appropriate cytotoxic T-cells. Thus, neuronal MHC-I can trigger antigenic response, and catecholamine neurons may be particularly susceptible to T cell-mediated cytotoxic attack.
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                Author and article information

                Contributors
                ds43@cumc.columbia.edu
                luigi.zecca@itb.cnr.it
                Journal
                NPJ Parkinsons Dis
                NPJ Parkinsons Dis
                NPJ Parkinson's Disease
                Nature Publishing Group UK (London )
                2373-8057
                10 April 2018
                10 April 2018
                2018
                : 4
                Affiliations
                [1 ]ISNI 0000 0000 8499 1112, GRID grid.413734.6, Department of Psychiatry, Columbia University Medical Center , , New York State Psychiatric Institute, ; New York, NY USA
                [2 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Department of Neurology, , Columbia University Medical Center, ; New York, NY USA
                [3 ]ISNI 0000 0001 2285 2675, GRID grid.239585.0, Department of Pharmacology, , Columbia University Medical Center, ; New York, NY USA
                [4 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, The Royal’s Institute of Mental Health Research, , Affiliated with the University of Ottawa, ; Ottawa, ON Canada
                [5 ]ISNI 0000 0004 1762 5736, GRID grid.8982.b, Department of Chemistry, , University of Pavia, ; Pavia, Italy
                [6 ]Parkinson Institute, ASST “Gaetano Pini-CTO”, Milan, Italy
                [7 ]ISNI 0000 0001 2222 1582, GRID grid.266097.c, Center for Advanced NeuroImaging, , University of California Riverside, ; Riverside, CA USA
                [8 ]ISNI 0000 0001 2222 1582, GRID grid.266097.c, Department of Bioengineering, , University of California Riverside, ; Riverside, CA USA
                [9 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Institute of Biomedical Technologies, , National Research Council of Italy, ; Milan, Italy
                [10 ]Department of Neurology, University Hospital and Julius-Maximillian-University, Wuerzburg, Germany
                Article
                47
                10.1038/s41531-018-0047-3
                5893576
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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