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Imaging Parkinsonian Pathology in Substantia Nigra with MRI

  • Daniel E. Huddleston
  • Jason Langley
  • Petr Dusek
  • Naying He
  • Carlos C. Faraco
  • Bruce Crosson
  • Stewart Factor
  • Xiaoping P. Hu
Neuroimaging (T Massoud, Section Editor)
  • 121 Downloads
Part of the following topical collections:
  1. Neuroimaging

Abstract

Purpose of Review

The substantia nigra pars compacta (SNc) and its projection to the striatum undergo profound degeneration in Parkinson’s disease (PD). Literature on imaging PD-related changes in the nigrostriatal system using iron-sensitive and diffusion-sensitive MRI contrasts has been contentious, with both negative and positive results reported in each contrast. These incompatible findings may be due to the inaccurate placement of regions of interest for the SNc.

Recent Findings

Histologically, SNc is characterized by the presence of melanized dopamine neurons, whereas the substantia nigra pars reticulata is characterized by high iron content. Despite this histology, previous studies have frequently relied upon iron-sensitive MRI contrast when segmenting the SNc. This is also problematic since recent work found iron-sensitive and neuromelanin-sensitive contrasts are largely non-overlapping in substantia nigra. Since neuromelanin-sensitive MRI contrast colocalizes with the melanized dopamine neurons of the SNc upon radiologic–histologic correlation, the use of neuromelanin-sensitive MRI will allow for accurate localization of SNc and better capture parkinsonian pathobiology than iron-sensitive MRI.

Summary

This article outlines iron-sensitive and diffusion-sensitive MRI contrasts, and provides an overview of neuromelanin-sensitive MRI techniques. The application of these techniques to image parkinsonian pathobiology in substantia nigra is then reviewed, with a focus on neuromelanin-sensitive imaging methods for the accurate and reproducible study of PD-related changes in SNc. These advances may help resolve current controversies surrounding MRI investigations of substantia nigra in PD and related disorders.

Keywords

Neuromelanin Substantia nigra Parkinson’s disease Neuromelanin-sensitive MRI Iron 

Notes

Acknowledgements

Xiaoping Hu and Daniel E. Huddleston receive support from the Michael J. Fox Foundation (MJF 10854). Petr Dusek is supported by Czech Science Foundation (grant nr. 16-07879S) and Czech Ministry of Health (grant nr. 15-25602A). Bruce Crosson receives support from the Rehabilitation Research & Development Service of the Department of Veterans Affairs Office of Research and Development (award nr. B6364-L).

Compliance with Ethical Guidelines

Conflict of interest

Daniel E. Huddleston, Jason Langley, Petr Dusek, Naying He, Carlos C. Faraco, Bruce Crosson, Stewart Factor, and Xiaoping Hu each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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  1. 1.
    Guitart-Masip M, Huys QJ, Fuentemilla L, Dayan P, Duzel E, Dolan RJ. Go and no-go learning in reward and punishment: interactions between affect and effect. NeuroImage. 2012;62(1):154–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Kimura K, Hikida T, Yawata S, Yamaguchi T, Nakanishi S. Pathway-specific engagement of ephrinA5-EphA4/EphA5 system of the substantia nigra pars reticulata in cocaine-induced responses. Proc Natl Acad Sci USA. 2011;108(24):9981–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Schiffer AM, Ahlheim C, Wurm MF, Schubotz RI. Surprised at all the entropy: hippocampal, caudate and midbrain contributions to learning from prediction errors. PLoS ONE. 2012;7(5):e36445.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Beckstead RM, Domesick VB, Nauta WJ. Efferent connections of the substantia nigra and ventral tegmental area in the rat. Brain Res. 1979;175(2):191–217.PubMedCrossRefGoogle Scholar
  5. 5.
    Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat. 2003;26(4):317–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Atherton JF, Bevan MD. Ionic mechanisms underlying autonomous action potential generation in the somata and dendrites of GABAergic substantia nigra pars reticulata neurons in vitro. J Neurosci. 2005;25(36):8272–81.PubMedCrossRefGoogle Scholar
  7. 7.
    Snyder AM, Connor JR. Iron, the substantia nigra and related neurological disorders. Biochim Biophys Acta. 2009;1790(7):606–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28 K) immunohistochemistry. Brain. 1999;122(Pt 8):1421–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol. 1978;14(4):633–43.PubMedGoogle Scholar
  10. 10.
    Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, et al. Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J Neurochem. 2008;106(4):1866–75.PubMedGoogle Scholar
  11. 11.
    Zucca FA, Segura-Aguilar J, Ferrari E, Munoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119.PubMedCrossRefGoogle Scholar
  12. 12.
    Zecca L, Gallorini M, SchuÈnemann V, Trautwein AX, Gerlach M, Riederer P, et al. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes. J Neurochem. 2001;76(6):1766–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Zecca L, Stroppolo A, Gatti A, Tampellini D, Toscani M, Gallorini M, et al. The role of iron and copper molecules in the neuronal vulnerability of locus coeruleus and substantia nigra during aging. Proc Natl Acad Sci USA. 2004;101(26):9843–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sulzer D, Bogulavsky J, Larsen KE, Behr G, Karatekin E, Kleinman MH, et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc Natl Acad Sci USA. 2000;97(22):11869–74.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Fenichel GM, Bazelon M. Studies on neuromelanin. II. Melanin in the brainstems of infants and children. Neurology. 1968;18(8):817–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Cowen D. The melanoneurons of the human cerebellum (nucleus pigmentosus cerebellaris) and homologues in the monkey. J Neuropathol Exp Neurol. 1986;45(3):205–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Ma SY, Roytt M, Collan Y, Rinne JO. Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol. 1999;25(5):394–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Manaye KF, McIntire DD, Mann DM, German DC. Locus coeruleus cell loss in the aging human brain: a non-random process. J Comp Neurol. 1995;358(1):79–87.PubMedCrossRefGoogle Scholar
  19. 19.
    Riederer P, Wuketich S. Time course of nigrostriatal degeneration in parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm. 1976;38(3–4):277–301.PubMedCrossRefGoogle Scholar
  20. 20.
    Halliday GM, McRitchie DA, Cartwright H, Pamphlett R, Hely MA, Morris JG. Midbrain neuropathology in idiopathic Parkinson’s disease and diffuse Lewy body disease. J Clin Neurosci. 1996;3(1):52–60.PubMedCrossRefGoogle Scholar
  21. 21.
    Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron. 2009;62(2):218–29.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Damier P, Hirsch EC, Agid Y, Graybiel AM. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain. 1999;122(Pt 8):1437–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain. 1991;114(Pt 5):2283–301.PubMedCrossRefGoogle Scholar
  24. 24.
    Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature. 1988;334(6180):345–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE, et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain. 1991;114(Pt 4):1953–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Dexter DT, Wells FR, Agid F, Agid Y, Lees AJ, Jenner P, et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet. 1987;2(8569):1219–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Witoszynskyj S, Rauscher A, Reichenbach JR, Barth M. Phase unwrapping of MR images using Phi UN–a fast and robust region growing algorithm. Med Image Anal. 2009;13(2):257–68.PubMedCrossRefGoogle Scholar
  28. 28.
    Morris CM, Edwardson JA. Iron histochemistry of the substantia nigra in Parkinson’s disease. Neurodegeneration. 1994;3(4):277–82.PubMedGoogle Scholar
  29. 29.
    Zucca FA, Segura-Aguilar J, Ferrari E, Munoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2015;155:96–119.PubMedCrossRefGoogle Scholar
  30. 30.
    Planetta PJ, Ofori E, Pasternak O, Burciu RG, Shukla P, DeSimone JC, et al. Free-water imaging in Parkinson’s disease and atypical parkinsonism. Brain. 2016;139(Pt 2):495–508.PubMedCrossRefGoogle Scholar
  31. 31.
    Urrutia PJ, Mena NP, Nunez MT. The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol. 2014;5:38.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Walsh S, Finn DP, Dowd E. Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson’s disease in the rat. Neuroscience. 2011;175:251–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Faucheux BA, Bonnet AM, Agid Y, Hirsch EC. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet. 1999;353(9157):981–2.PubMedCrossRefGoogle Scholar
  34. 34.
    Desai Bradaric B, Patel A, Schneider JA, Carvey PM, Hendey B. Evidence for angiogenesis in Parkinson’s disease, incidental Lewy body disease, and progressive supranuclear palsy. J Neural Transm. 2012;119(1):59–71.PubMedCrossRefGoogle Scholar
  35. 35.
    Strafella AP, Bohnen NI, Perlmutter JS, Eidelberg D, Pavese N, Van Eimeren T, et al. Molecular imaging to track Parkinson’s disease and atypical parkinsonisms: new imaging frontiers. Mov Disord. 2017;32(2):181–92.PubMedCrossRefGoogle Scholar
  36. 36.
    Walter U. Transcranial brain sonography findings in Parkinson’s disease: implications for pathogenesis, early diagnosis and therapy. Expert Rev Neurother. 2009;9(6):835–46.PubMedCrossRefGoogle Scholar
  37. 37.
    Niehaus L, Boelmans K. Diagnosis of Parkinson’s disease–transcranial sonography in relation to MRI. Int Rev Neurobiol. 2010;90:63–79.PubMedCrossRefGoogle Scholar
  38. 38.
    Sasaki M, Shibata E, Tohyama K, Takahashi J, Otsuka K, Tsuchiya K, et al. Neuromelanin magnetic resonance imaging of locus ceruleus and substantia nigra in Parkinson’s disease. NeuroReport. 2006;17(11):1215–8.PubMedCrossRefGoogle Scholar
  39. 39.
    •• Keren NI, Taheri S, Vazey EM, Morgan PS, Granholm AC, Aston-Jones GS, et al. Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. Neuroimage. 2015;113(1):235–45. This manuscript compares M-MRI hyperintense signal with histology and found neuromelanin containing neurons colocalize with hyperintense signal in NM-MRI images. Google Scholar
  40. 40.
    Kitao S, Matsusue E, Fujii S, Miyoshi F, Kaminou T, Kato S, et al. Correlation between pathology and neuromelanin MR imaging in Parkinson’s disease and dementia with Lewy bodies. Neuroradiology. 2013;55(8):947–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Bolding MS, Reid MA, Avsar KB, Roberts RC, Gamlin PD, Gawne TJ, et al. Magnetic transfer contrast accurately localizes substantia nigra confirmed by histology. Biol Psychiatry. 2013;73(3):289–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Dixon WT, Engels H, Castillo M, Sardashti M. Incidental magnetization transfer contrast in standard multislice imaging. Magn Reson Imaging. 1990;8(4):417–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen X, Huddleston DE, Langley J, Ahn S, Barnum CJ, Factor SA, et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magn Reson Imaging. 2014;32(10):1301–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP. T1-Weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson’s disease. Mov Disord. 2011;26(9):1633–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Trujillo P, Smith AK, Summers PE, Mainardi LM, Cerutti S, Smith SA, et al. High-resolution quantitative imaging of the substantia nigra. Conf Proc IEEE Eng Med Biol Soc. 2015;2015:5428–31.PubMedGoogle Scholar
  46. 46.
    Trujillo P, Summers PE, Ferrari E, Zucca FA, Sturini M, Mainardi LT, et al. Contrast mechanisms associated with neuromelanin-MRI. Magn Reson Med. 2017;78(5):1790–800.PubMedCrossRefGoogle Scholar
  47. 47.
    Ogisu K, Kudo K, Sasaki M, Sakushima K, Yabe I, Sasaki H, et al. 3D neuromelanin-sensitive magnetic resonance imaging with semi-automated volume measurement of the substantia nigra pars compacta for diagnosis of Parkinson’s disease. Neuroradiology. 2013;55(6):719–24.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakane T, Nihashi T, Kawai H, Naganawa S. Visualization of neuromelanin in the Substantia nigra and locus ceruleus at 1.5T using a 3D-gradient echo sequence with magnetization transfer contrast. Magn Reson Med. 2008;7(4):205–10.CrossRefGoogle Scholar
  49. 49.
    Gorell JM, Ordidge RJ, Brown GG, Deniau JC, Buderer NM, Helpern JA. Increased iron-related MRI contrast in the substantia nigra in Parkinson’s disease. Neurology. 1995;45(6):1138–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Haacke EM, Xu Y, Cheng Y-CN, Reichenbach JR. Susceptibility weighted imaging (SWI). Magn Reson Med. 2004;52:612–8.PubMedCrossRefGoogle Scholar
  51. 51.
    de Rochefort L, Brown R, Prince MR, Wang Y. Quantitative MR susceptibility mapping using piece-wise constant regularized inversion of the magnetic field. Magn Reson Med. 2008;60(4):1003–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Li W, Wu B, Liu C. Quantitative susceptibility mapping of human brain reflects spatial variation in tissue composition. NeuroImage. 2011;55(4):1645–56.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Liu T, Spincemaille P, de Rochefort L, Kressler B, Wang Y. Calculation of susceptibility through multiple orientation sampling (COSMOS): a method for conditioning the inverse problem from measured magnetic field map to susceptibility source image in MRI. Magn Reson Med. 2009;61(1):196–204.PubMedCrossRefGoogle Scholar
  54. 54.
    He N, Ling H, Ding B, Huang J, Zhang Y, Zhang Z, et al. Region-specific disturbed iron distribution in early idiopathic Parkinson’s disease measured by quantitative susceptibility mapping. Hum Brain Mapp. 2015;36(11):4407–20.PubMedCrossRefGoogle Scholar
  55. 55.
    Langkammer C, Schweser F, Krebs N, Deistung A, Goessler W, Scheurer E, et al. Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. Neuroimage. 2012;62(3):1593–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Sun H, Walsh AJ, Lebel RM, Blevins G, Catz I, Lu JQ, et al. Validation of quantitative susceptibility mapping with Perls’ iron staining for subcortical gray matter. Neuroimage. 2015;105:486–92.PubMedCrossRefGoogle Scholar
  57. 57.
    Zheng W, Nichol H, Liu S, Cheng YC, Haacke EM. Measuring iron in the brain using quantitative susceptibility mapping and X-ray fluorescence imaging. Neuroimage. 2013;78:68–74.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    House MJ, St Pierre TG, Kowdley KV, Montine T, Connor J, Beard J, et al. Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from alzheimer’s disease patients. Magn Reson Med. 2007;57(1):172–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Deistung A, Schafer A, Schweser F, Biedermann U, Turner R, Reichenbach JR. Toward in vivo histology: a comparison of quantitative susceptibility mapping (QSM) with magnitude-, phase-, and R2*-imaging at ultra-high magnetic field strength. Neuroimage. 2013;65:299–314.PubMedCrossRefGoogle Scholar
  60. 60.
    Usunoff KG, Itzev DE, Ovtscharoff WA, Marani E. Neuromelanin in the human brain: a review and atlas of pigmented cells in the substantia nigra. Arch Physiol Biochem. 2002;110(4):257–369.PubMedCrossRefGoogle Scholar
  61. 61.
    Langley J, Huddleston DE, Chen X, Sedlacik J, Zachariah N, Hu X. A multicontrast approach for comprehensive imaging of substantia nigra. Neuroimage. 2015;112:7–13.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Gramsch C, Reuter I, Kraff O, Quick HH, Tanislav C, Roessler F, et al. Nigrosome 1 visibility at susceptibility weighted 7T MRI-A dependable diagnostic marker for Parkinson’s disease or merely an inconsistent, age-dependent imaging finding? PLoS ONE. 2017;12(10):e0185489.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Blazejewska AI, Schwarz ST, Pitiot A, Stephenson MC, Lowe J, Bajaj N, et al. Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI. Neurology. 2013;81(6):534–40.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Massey LA, Miranda MA, Al-Helli O, Parkes HG, Thornton JS, So PW, et al. 9.4 T MR microscopy of the substantia nigra with pathological validation in controls and disease. Neuroimage Clin. 2017;13:154–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Ohtsuka C, Sasaki M, Konno K, Koide M, Kato K, Takahashi J, et al. Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson’s disease using neuromelanin-sensitive MR imaging. Neurosci Lett. 2013;541:93–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Matsuura K, Maeda M, Tabei KI, Umino M, Kajikawa H, Satoh M, et al. A longitudinal study of neuromelanin-sensitive magnetic resonance imaging in Parkinson’s disease. Neurosci Lett. 2016;633:112–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Castellanos G, Fernandez-Seara MA, Lorenzo-Betancor O, Ortega-Cubero S, Puigvert M, Uranga J, et al. Automated Neuromelanin Imaging as a Diagnostic Biomarker for Parkinson’s disease. Mov Disord. 2015;30(7):945–52.PubMedCrossRefGoogle Scholar
  68. 68.
    Reimao S, Pita Lobo P, Neutel D, Correia Guedes L, Coelho M, Rosa MM, et al. Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson’s disease patients. Eur J Neurol. 2015;22(3):540–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Kashihara K, Shinya T, Higaki F. Neuromelanin magnetic resonance imaging of nigral volume loss in patients with Parkinson’s disease. J Clin Neurosci. 2011;18(8):1093–6.PubMedCrossRefGoogle Scholar
  70. 70.
    Schwarz ST, Xing Y, Tomar P, Bajaj N, Auer DP. In vivo assessment of brainstem depigmentation in parkinson disease: potential as a severity marker for multicenter studies. Radiology. 2017;283(3):789–98.PubMedCrossRefGoogle Scholar
  71. 71.
    Isaias IU, Trujillo P, Summers P, Marotta G, Mainardi L, Pezzoli G, et al. Neuromelanin imaging and dopaminergic loss in Parkinson’s disease. Front Aging Neurosci. 2016;8:196.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Reimao S, Pita Lobo P, Neutel D, Guedes LC, Coelho M, Rosa MM, et al. Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson’s disease. Mov Disord. 2015;30(7):953–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Kashihara K, Shinya T, Higaki F. Reduction of neuromelanin-positive nigral volume in patients with MSA, PSP and CBD. Intern Med. 2011;50(16):1683–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Ohtsuka C, Sasaki M, Konno K, Kato K, Takahashi J, Yamashita F, et al. Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. Parkinsonism Relat Disord. 2014;20(7):755–60.PubMedCrossRefGoogle Scholar
  75. 75.
    Miyoshi F, Ogawa T, Kitao SI, Kitayama M, Shinohara Y, Takasugi M, et al. Evaluation of Parkinson disease and Alzheimer disease with the use of neuromelanin MR imaging and (123)I-metaiodobenzylguanidine scintigraphy. AJNR. 2013;34(11):2113–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Wypijewska A, Galazka-Friedman J, Bauminger ER, Wszolek ZK, Schweitzer KJ, Dickson DW, et al. Iron and reactive oxygen species activity in parkinsonian substantia nigra. Parkinsonism Relat Disord. 2010;16(5):329–33.PubMedCrossRefGoogle Scholar
  77. 77.
    Baudrexel S, Nurnberger L, Rub U, Seifried C, Klein JC, Deller T, et al. Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson’s disease. Neuroimage. 2010;51(2):512–20.PubMedCrossRefGoogle Scholar
  78. 78.
    Du G, Lewis MM, Styner M, Shaffer ML, Sen S, Yang QX, et al. Combined R2* and diffusion tensor imaging changes in the substantia nigra in Parkinson’s disease. Mov Disord. 2011;26(9):1627–32.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Graham JM, Paley MN, Grunewald RA, Hoggard N, Griffiths PD. Brain iron deposition in Parkinson’s disease imaged using the PRIME magnetic resonance sequence. Brain. 2000;123(Pt 12):2423–31.PubMedCrossRefGoogle Scholar
  80. 80.
    Kosta P, Argyropoulou MI, Markoula S, Konitsiotis S. MRI evaluation of the basal ganglia size and iron content in patients with Parkinson’s disease. J Neurol. 2006;253(1):26–32.PubMedCrossRefGoogle Scholar
  81. 81.
    Martin WR, Wieler M, Gee M. Midbrain iron content in early Parkinson disease: a potential biomarker of disease status. Neurology. 2008;70(16 Pt 2):1411–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Peran P, Cherubini A, Assogna F, Piras F, Quattrocchi C, Peppe A, et al. Magnetic resonance imaging markers of Parkinson’s disease nigrostriatal signature. Brain. 2010;133(11):3423–33.PubMedCrossRefGoogle Scholar
  83. 83.
    Wallis LI, Paley MN, Graham JM, Grunewald RA, Wignall EL, Joy HM, et al. MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging. 2008;28(5):1061–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Aquino D, Contarino V, Albanese A, Minati L, Farina L, Grisoli M, et al. Substantia nigra in Parkinson’s disease: a multimodal MRI comparison between early and advanced stages of the disease. Neurol Sci. 2014;35(5):753–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Focke NK, Helms G, Pantel PM, Scheewe S, Knauth M, Bachmann CG, et al. Differentiation of typical and atypical Parkinson syndromes by quantitative MR imaging. AJNR. 2011;32(11):2087–92.PubMedCrossRefGoogle Scholar
  86. 86.
    Mondino F, Filippi P, Magliola U, Duca S. Magnetic resonance relaxometry in Parkinson’s disease. Neurol Sci. 2002;23(Suppl 2):S87–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Vymazal J, Righini A, Brooks RA, Canesi M, Mariani C, Leonardi M, et al. T1 and T2 in the brain of healthy subjects, patients with Parkinson disease, and patients with multiple system atrophy: relation to iron content. Radiology. 1999;211(2):489–95.PubMedCrossRefGoogle Scholar
  88. 88.
    Ordidge RJ, Gorell JM, Deniau JC, Knight RA, Helpern JA. Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla. Magn Reson Med. 1994;32(3):335–41.PubMedCrossRefGoogle Scholar
  89. 89.
    Gupta D, Saini J, Kesavadas C, Sarma PS, Kishore A. Utility of susceptibility-weighted MRI in differentiating Parkinson’s disease and atypical parkinsonism. Neuroradiology. 2010;52(12):1087–94.PubMedCrossRefGoogle Scholar
  90. 90.
    Dashtipour K, Liu M, Kani C, Dalaie P, Obenaus A, Simmons D, et al. Iron Accumulation Is Not Homogenous among Patients with Parkinson’s disease. Parkinson’s Dis. 2015;2015:324843.Google Scholar
  91. 91.
    Haller S, Badoud S, Nguyen D, Barnaure I, Montandon ML, Lovblad KO, et al. Differentiation between Parkinson disease and other forms of Parkinsonism using support vector machine analysis of susceptibility-weighted imaging (SWI): initial results. Eur Radiol. 2013;23(1):12–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Lotfipour AK, Wharton S, Schwarz ST, Gontu V, Schafer A, Peters AM, et al. High resolution magnetic susceptibility mapping of the substantia nigra in Parkinson’s disease. J Magn Reson Imaging. 2012;35(1):48–55.PubMedCrossRefGoogle Scholar
  93. 93.
    Lim IA, Faria AV, Li X, Hsu JT, Airan RD, Mori S, et al. Human brain atlas for automated region of interest selection in quantitative susceptibility mapping: application to determine iron content in deep gray matter structures. NeuroImage. 2013;82:449–69.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lim IA, Li X, Jones CK, Farrell JA, Vikram DS, van Zijl PC. Quantitative magnetic susceptibility mapping without phase unwrapping using WASSR. NeuroImage. 2014;86:265–79.PubMedCrossRefGoogle Scholar
  95. 95.
    Ryvlin P, Broussolle E, Piollet H, Viallet F, Khalfallah Y, Chazot G. Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson’s disease. Arch Neurol. 1995;52(6):583–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, Durif F. Is R2* a new MRI biomarker for the progression of Parkinson’s disease? A longitudinal follow-up. PLoS ONE. 2013;8(3):e57904.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Langley J, Huddleston DE, Sedlacik J, Boelmans K, Hu XP. Parkinson’s disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta. Mov Disord. 2017;32(3):441–9.PubMedCrossRefGoogle Scholar
  98. 98.
    • Huddleston DE, Langley J, Sedlacik J, Boelmans K, Factor SA, Hu XP. In vivo detection of lateral-ventral tier nigral degeneration in Parkinson’s disease. Hum Brain Mapp. 2017;38(5):2627–34. Histology findings of the substantia nigra in Parkinson’s disease show selective loss of melanized dopamine neurons in the lateral-ventral SNc. This work provides the first direct imaging evidence showing a reduction of neuromelanin-sensitive signal in lateral-ventral tier of substantia nigra.Google Scholar
  99. 99.
    German DC, Manaye K, Smith WK, Woodward DJ, Saper CB. Midbrain dopaminergic cell loss in Parkinson’s disease: computer visualization. Ann Neurol. 1989;26(4):507–14.PubMedCrossRefGoogle Scholar
  100. 100.
    Hassler R. Zur Pathologie der Paralysis agitains und des postenzephalitischen Parkinsonismus. J Psychol Neurol. 1938;48:387–476.Google Scholar
  101. 101.
    Schwarz ST, Afzal M, Morgan PS, Bajaj N, Gowland PA, Auer DP. The ‘swallow tail’ appearance of the healthy nigrosome—a new accurate test of Parkinson’s disease: a case-control and retrospective cross-sectional MRI study at 3T. PLoS ONE. 2014;9(4):e93814.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Fu KA, Nathan R, Dinov ID, Li J, Toga AW. T2-imaging changes in the nigrosome-1 relate to clinical measures of Parkinson’s disease. Front Neurol. 2016;7:174.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Mahlknecht P, Krismer F, Poewe W, Seppi K. Meta-analysis of dorsolateral nigral hyperintensity on magnetic resonance imaging as a marker for Parkinson’s disease. Mov Disord. 2017;32(4):619–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Meijer FJ, Steens SC, van Rumund A, van Cappellen, van Walsum AM, Kusters B, Esselink RA, et al. Nigrosome-1 on susceptibility weighted imaging to differentiate Parkinson’s disease from atypical parkinsonism: an in vivo and ex vivo pilot study. Pol J Radiol. 2016;81:363–9.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Schmidt MA, Engelhorn T, Marxreiter F, Winkler J, Lang S, Kloska S, et al. Ultra high-field SWI of the substantia nigra at 7T: reliability and consistency of the swallow-tail sign. BMC Neurol. 2017;17(1):194.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Reimao S, Ferreira S, Nunes RG, Pita Lobo P, Neutel D, Abreu D, et al. Magnetic resonance correlation of iron content with neuromelanin in the substantia nigra of early-stage Parkinson’s disease. Eur J Neurol. 2016;23(2):368–74.PubMedCrossRefGoogle Scholar
  107. 107.
    Blain CR, Barker GJ, Jarosz JM, Coyle NA, Landau S, Brown RG, et al. Measuring brain stem and cerebellar damage in parkinsonian syndromes using diffusion tensor MRI. Neurology. 2006;67(12):2199–205.PubMedCrossRefGoogle Scholar
  108. 108.
    Schocke MF, Seppi K, Esterhammer R, Kremser C, Jaschke W, Poewe W, et al. Diffusion-weighted MRI differentiates the Parkinson variant of multiple system atrophy from PD. Neurology. 2002;58(4):575–80.PubMedCrossRefGoogle Scholar
  109. 109.
    Langley J, Huddleston DE, Merritt M, Chen X, McMurray R, Silver M, et al. Diffusion tensor imaging of the substantia nigra in Parkinson’s disease revisited. Hum Brain Mapp. 2016;37(7):2547–56.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Chan LL, Rumpel H, Yap K, Lee E, Loo HV, Ho GL, et al. Case control study of diffusion tensor imaging in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2007;78(12):1383–6.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Vaillancourt DE, Spraker MB, Prodoehl J, Abraham I, Corcos DM, Zhou XJ, et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology. 2009;72(16):1378–84.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wang JJ, Lin WY, Lu CS, Weng YH, Ng SH, Wang CH, et al. Parkinson disease: diagnostic utility of diffusion kurtosis imaging. Radiology. 2011;261(1):210–7.PubMedCrossRefGoogle Scholar
  113. 113.
    Menke RA, Scholz J, Miller KL, Deoni S, Jbabdi S, Matthews PM, et al. MRI characteristics of the substantia nigra in Parkinson’s disease: a combined quantitative T1 and DTI study. NeuroImage. 2009;47(2):435–41.PubMedCrossRefGoogle Scholar
  114. 114.
    Schwarz ST, Abaei M, Gontu V, Morgan PS, Bajaj N, Auer DP. Diffusion tensor imaging of nigral degeneration in Parkinson’s disease: a region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis. Neuroimage Clin. 2013;3:481–8.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Ziegler E, Rouillard M, Andre E, Coolen T, Stender J, Balteau E, et al. Mapping track density changes in nigrostriatal and extranigral pathways in Parkinson’s disease. Neuroimage. 2014;99:498–508.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Fujiwara S, Uhrig L, Amadon A, Jarraya B, Le Bihan D. Quantification of iron in the non-human primate brain with diffusion-weighted magnetic resonance imaging. Neuroimage. 2014;102(2):789–97.PubMedCrossRefGoogle Scholar
  117. 117.
    Kamagata K, Hatano T, Okuzumi A, Motoi Y, Abe O, Shimoji K, et al. Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson disease. Eur Radiol. 2016;26(8):2567–77.PubMedCrossRefGoogle Scholar
  118. 118.
    Ofori E, Pasternak O, Planetta PJ, Burciu R, Snyder A, Febo M, et al. Increased free water in the substantia nigra of Parkinson’s disease: a single-site and multi-site study. Neurobiol Aging. 2015;36(2):1097–104.PubMedCrossRefGoogle Scholar
  119. 119.
    Theisen F, Leda R, Pozorski V, Oh JM, Adluru N, Wong R, et al. Evaluation of striatonigral connectivity using probabilistic tractography in Parkinson’s disease. Neuroimage Clin. 2017;16:557–63.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kim M, Park H. Structural connectivity profile of scans without evidence of dopaminergic deficit (SWEDD) patients compared to normal controls and Parkinson’s disease patients. Springerplus. 2016;5(1):1421.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Yoshikawa K, Nakata Y, Yamada K, Nakagawa M. Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI. J Neurol Neurosurg Psychiatry. 2004;75(3):481–4.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–70.PubMedCrossRefGoogle Scholar
  123. 123.
    Zhang Y, Wu IW, Buckley S, Coffey CS, Foster E, Mendick S, et al. Diffusion tensor imaging of the nigrostriatal fibers in Parkinson’s disease. Mov Disord. 2015;30(9):1229–36.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Menke RA, Jbabdi S, Miller KL, Matthews PM, Zarei M. Connectivity-based segmentation of the substantia nigra in human and its implications in Parkinson’s disease. NeuroImage. 2010;52(4):1175–80.PubMedCrossRefGoogle Scholar
  125. 125.
    Marras C, Rochon P, Lang AE. Predicting motor decline and disability in Parkinson disease: a systematic review. Arch Neurol. 2002;59(11):1724–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Thenganatt MA, Jankovic J. Parkinson disease subtypes. JAMA Neurol. 2014;71(4):499–504.PubMedCrossRefGoogle Scholar
  127. 127.
    von Coelln R, Shulman LM. Clinical subtypes and genetic heterogeneity: of lumping and splitting in Parkinson disease. Curr Opin Neurol. 2016;29(6):727–34.CrossRefGoogle Scholar
  128. 128.
    Espay AJ, Schwarzschild MA, Tanner CM, Fernandez HH, Simon DK, Leverenz JB, et al. Biomarker-driven phenotyping in Parkinson’s disease: a translational missing link in disease-modifying clinical trials. Mov Disord. 2017;32(3):319–24.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Schillaci O, Chiaravalloti A, Pierantozzi M, Di Pietro B, Koch G, Bruni C, et al. Different patterns of nigrostriatal degeneration in tremor type versus the akinetic-rigid and mixed types of Parkinson’s disease at the early stages: molecular imaging with 123I-FP-CIT SPECT. Int J Mol Med. 2011;28(5):881–6.PubMedGoogle Scholar
  130. 130.
    Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 2011;69(2):269–81.PubMedCrossRefGoogle Scholar
  131. 131.
    Lewis MM, Du G, Sen S, Kawaguchi A, Truong Y, Lee S, et al. Differential involvement of striato- and cerebello-thalamo-cortical pathways in tremor- and akinetic/rigid-predominant Parkinson’s disease. Neuroscience. 2011;177:230–9.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ni Z, Pinto AD, Lang AE, Chen R. Involvement of the cerebellothalamocortical pathway in Parkinson disease. Ann Neurol. 2010;68(6):816–24.PubMedCrossRefGoogle Scholar
  133. 133.
    He N, Huang P, Ling H, Langley J, Liu C, Ding B, et al. Dentate nucleus iron deposition is a potential biomarker for tremor-dominant Parkinson’s disease. NMR Biomed. 2017.  https://doi.org/10.1002/nbm.3554.Google Scholar
  134. 134.
    Galazka-Friedman J, Bauminger ER, Friedman A, Barcikowska M, Hechel D, Nowik I. Iron in parkinsonian and control substantia nigra—a Mossbauer spectroscopy study. Mov Disord. 1996;11(1):8–16.PubMedCrossRefGoogle Scholar
  135. 135.
    Uitti RJ, Rajput AH, Rozdilsky B, Bickis M, Wollin T, Yuen WK. Regional metal concentrations in Parkinson’s disease, other chronic neurological diseases, and control brains. Can J Neurol Sci. 1989;16(3):310–4.PubMedCrossRefGoogle Scholar
  136. 136.
    Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K. Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology. 1995;45(1):182–4.PubMedCrossRefGoogle Scholar
  137. 137.
    Guiney SJ, Adlard PA, Bush AI, Finkelstein DI, Ayton S. Ferroptosis and cell death mechanisms in Parkinson’s disease. Neurochem Int. 2017;104:34–48.PubMedCrossRefGoogle Scholar
  138. 138.
    Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211.PubMedCrossRefGoogle Scholar
  139. 139.
    Zarow C, Lyness SA, Mortimer JA, Chui HC. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol. 2003;60(3):337–41.PubMedCrossRefGoogle Scholar
  140. 140.
    Benarroch EE. The locus ceruleus norepinephrine system: functional organization and potential clinical significance. Neurology. 2009;73(20):1699–704.PubMedCrossRefGoogle Scholar
  141. 141.
    Burke RE, Dauer WT, Vonsattel JPG. A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol. 2008;64(5):485–91.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Jellinger K. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol. 2008;116(1):1–16.PubMedCrossRefGoogle Scholar
  143. 143.
    Langley J, Huddleston DE, Liu CJ, Hu X. Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. MAGMA. 2017;30(2):121–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Kaasinen V, Vahlberg T. Striatal dopamine in Parkinson disease: a meta-analysis of imaging studies. Ann Neurol. 2017;82(6):873–82.PubMedCrossRefGoogle Scholar
  145. 145.
    Kuya K, Ogawa T, Shinohara Y, Ishibashi M, Fujii S, Mukuda N, et al. Evaluation of Parkinson’s disease by neuromelanin-sensitive magnetic resonance imaging and (123)I-FP-CIT SPECT. Acta Radiol. 2017.  https://doi.org/10.1177/0284185117722812.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyEmory UniversityAtlantaUSA
  2. 2.Center for Advanced NeuroimagingUniversity of California RiversideRiversideUSA
  3. 3.Department of Neurology and Center of Clinical NeuroscienceCharles University, 1st Faculty of Medicine and General University Hospital in PraguePragueCzech Republic
  4. 4.Department of RadiologyCharles University, 1st Faculty of Medicine and General University Hospital in PraguePragueCzech Republic
  5. 5.Department of Radiology, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
  6. 6.Department of Radiology and Radiological ScienceVanderbilt University Medical CenterNashvilleUSA
  7. 7.Department of Veterans Affairs Center for Visual and Neurocognitive RehabilitationAtlanta Veterans Affairs Medical CenterDecaturUSA
  8. 8.Department of PsychologyGeorgia State UniversityAtlantaUSA
  9. 9.Department of BioengineeringUniversity of California RiversideRiversideUSA

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