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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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Neuromelanin Detection by Magnetic Resonance Imaging (MRI) and Its Promise As a Biomarker for Parkinson’S Disease www.nature.com/npjparkd REVIEW ARTICLE OPEN Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease David Sulzer1,2,3, Clifford Cassidy4, Guillermo Horga1, Un Jung Kang2, Stanley Fahn2, Luigi Casella5, Gianni Pezzoli6, Jason Langley7, Xiaoping P. Hu8, Fabio A. Zucca9, Ioannis U. Isaias10 and Luigi Zecca9 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. npj Parkinson’s Disease (2018) 4:11 ; doi:10.1038/s41531-018-0047-3 THE NEED TO DETECT PARKINSON’S DISEASE (PD) PRIOR TO decades. Moreover, not all people who develop PD have a prior THE ARRIVAL OF SYMPTOMS history of RBD. It is widely suspected that damage to dopaminer- Following the identification of alpha-synuclein mutations,1 var- gic axons may precede cell death, and single-photon emission iants of numerous genes have been associated with familial PD.2 computed tomography (SPECT) or positron emission tomography Many of these alleles exhibit low “penetrance”, as many who carry (PET) imaging for dopamine axon-associated labels such as the these variants never develop PD. There are moreover environ- dopamine transporter (DAT) or vesicular monoamine transporter 2 mental associations with PD, including pesticide or manganese (VMAT2) are promising, but these are expensive and involve exposure,3,4 but the majority of exposed individuals do not radiation exposure.8 Assays of PD-specific immunological develop PD. responses, including the presence of specific T cells populations,9 PD diagnosis occurs only when the motor symptoms are are promising, but as recently reviewed,10 the use of candidate apparent and 30% or more of the substantia nigra (SN) dopamine cytokine markers may not provide adequate differentiation neurons have already died.5 This presents a fundamental between multiple disorders. challenge to clinical treatment: while there are multiple promising An alternate approach is to examine the targeted neurons. The therapies under exploration, including the use of growth factors,6 presence of the dark neuromelanin (NM) pigment provides ion channel ligands,7 immune and gene therapies, antioxidants, the names “SN” and “locus coeruleus” (LC). About a century after and exercise regimes, such prophylactic approaches should begin the first description of PD,11 the disease was noticed to feature the early in the disease course, before many neurons are sick or dead. loss of the NM pigmented cells of the SN.12 These pigmented No useful test exists to diagnose PD prior to the arrival of motor neurons were eventually found to be dopaminergic.13 A similar symptoms. PD patients often exhibit early disease-associated loss occurs during PD of the pigmented noradrenergic neurons of features, including loss of smell, restless leg syndrome, anxiety, the LC (for a detailed review of targeted neurons in PD, see ref. 14). depression, and constipation and REM sleep behavior disorder, It took nearly another century to develop a means to detect but these are associated with many disorders. A high proportion these pigmented neurons in living patients. About 15 years ago, of individuals with rapid eye movement sleep behaviors disorders Zecca, Sulzer, and colleagues15 suggested from their measure- (RBD) develop synucleinopathies, but the progression occurs over ment of NM concentration in SN of normal and PD subjects that 1Department of Psychiatry, Columbia University Medical Center , New York State Psychiatric Institute, New York, NY, USA; 2Department of Neurology, Columbia University Medical Center, New York, NY, USA; 3Department of Pharmacology, Columbia University Medical Center, New York, NY, USA; 4The Royal’s Institute of Mental Health Research, Affiliated with the University of Ottawa, Ottawa, ON, Canada; 5Department of Chemistry, University of Pavia, Pavia, Italy; 6Parkinson Institute, ASST “Gaetano Pini-CTO”, Milan, Italy; 7Center for Advanced NeuroImaging, University of California Riverside, Riverside, CA, USA; 8Department of Bioengineering, University of California Riverside, Riverside, CA, USA; 9Institute of Biomedical Technologies, National Research Council of Italy, Milan, Italy and 10Department of Neurology, University Hospital and Julius-Maximillian-University, Wuerzburg, Germany Correspondence: David Sulzer ([email protected]) or Luigi Zecca ([email protected]) Received: 2 November 2017 Revised: 5 March 2018 Accepted: 8 March 2018 Published in partnership with the Parkinson’s Foundation Neuromelanin detection by magnetic resonance imaging D Sulzer et al. 2 “NM appears to be a good marker of damage to the SN pars human brain and is not found in SN.17,18 The melanosomes are compacta (SNc) in PD. As such, the development of NM in vivo secreted and then acquired by the pigmented cells. imaging techniques may offer diagnostic and disease staging NM uses a very different synthetic pathway (Fig. 1). The color measurements matching the available tools used to monitor and electron dense property of NM pigment is derived from the striatal dopamine depletion and offering the first direct approach conversion of dopamine, norepinephrine, and other catechola- to recognize and quantify nigral damage. The concentration mines in the cytosol by oxidation to semi-quinones and values of NM here described could be used for correlation with quinones.19 While tyrosinase is absent, other enzymes might be in vivo images of SN in normal and PD subjects. Further studies involved in NM synthesis (for an extensive review of possible should expand the above observations in other extrapyramidal enzymatic participation in NM synthesis, see refs. 20,21). The disorders to assess specificity of NM depletion and correlation catechol oxidation reaction may also occur non-enzymatically, and with other established markers of nigrostriatal dysfunction”. iron and other redox metals strongly promote the auto-oxidation Since that time, efforts by the authors and others have of catecholamine to quinones.19 introduced a magnetic resonance imaging (MRI) approach that NM pigment, while probably initially produced in the cytosol, is promises a means to assay individuals on their way to developing accumulated within autophagic organelles.22 In this macroauto- the disorder before most of these neurons have died. The current phagic pathway, multilamellar organelles known as autophago- results are promising, but much work remains before this somes envelop intracellular constituents and traffic to lysosomes, approach is adapted to the clinic. We discuss the rationale, with which they fuse (Fig. 1). Broadly, autophagosomes are theory, practice, and advantages and disadvantages of this produced in response to many forms of cellular stress, apparently approach, and offer suggestions on future research and potential including high levels of cytosolic dopamine, and so the presence use in therapy. of NM organelles may be both a sign of oxidative stress and a protective response to it. These NM-containing organelles possess abundant lipid bodies and soluble and pigment bound proteins (Fig. 2).23,24 NM PIGMENT IS SYNTHESIZED FROM OXIDIZED Notably, lipofuscin and ceroid pigment organelles also originate CATECHOLAMINES THAT ARE TRAPPED WITHIN AUTOPHAGIC in a similar manner, although their morphology differs from that ORGANELLES of NM-containing organelles.25 In each case, the lysosomes do not There are parallels between NM and the melanin pigments of skin, efficiently break down the pigments and they are accumulated 1234567890():,; hair, eyes, feathers, and squid ink, as both are produced as with age, unless the cells die, in which case specialized phagocytic oxidative products downstream from L-DOPA, and both classes of cells such as microglia or macrophages, which have far more pigments play protective roles against damage to the cytosol, in powerful degradation systems than neurons, destroy NM orga- the case of melanin by decreasing photodamage. Such catecho- nelles and the NM pigment itself; this process can be observed by lamine oxidation is a common way to produce pigment
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