Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease

Abstract

Parkinson disease (PD) is a progressive disorder characterized by dopaminergic neurodegeneration in the brain. The development of parkinsonism is preceded by a long prodromal phase, and >50% of dopaminergic neurons can be lost from the substantia nigra by the time of the initial diagnosis. Therefore, validation of in vivo imaging biomarkers for early diagnosis and monitoring of disease progression is essential for future therapeutic developments. PET and single-photon emission CT targeting the presynaptic terminals of dopaminergic neurons can be used for early diagnosis by detecting axonal degeneration in the striatum. However, these techniques poorly differentiate atypical parkinsonian syndromes from PD, and their availability is limited in clinical settings. Advanced MRI in which pathological changes in the substantia nigra are visualized with diffusion, iron-sensitive susceptibility and neuromelanin-sensitive sequences potentially represents a more accessible imaging tool. Although these techniques can visualize the classic degenerative changes in PD, they might be insufficient for phenotyping or prognostication of heterogeneous aspects of PD resulting from extranigral pathologies. The retina is an emerging imaging target owing to its pathological involvement early in PD, which correlates with brain pathology. Retinal optical coherence tomography (OCT) is a non-invasive technique to visualize structural changes in the retina. Progressive parafoveal thinning and fovea avascular zone remodelling, as revealed by OCT, provide potential biomarkers for early diagnosis and prognostication in PD. As we discuss in this Review, multimodal imaging of the substantia nigra and retina is a promising tool to aid diagnosis and management of PD.

Key points

  • Advanced nigral MRI techniques in Parkinson disease (PD) include diffusion tensor free water measurement, quantitative susceptibility mapping of iron signals, evaluation of nigrosome 1 (N1) loss on iron-sensitive sequences and quantification of neuromelanin loss on neuromelanin-sensitive sequences.

  • N1 signal loss and neuromelanin reduction in the substantia nigra pars compacta can be detected in prodromal PD, although longitudinal studies are required to validate this approach.

  • Multimodal imaging capturing pathological changes in the substantia nigra should substantially enhance diagnostic accuracy in early PD, and longitudinal multimodal MRI studies could provide essential pathophysiological insights and provide markers to monitor disease progression.

  • Visual disturbances observed in patients with PD are linked to retinal dopamine loss, which results in functional derangement of couplings between retinal cells and defective synaptic transmission.

  • Parafoveal inner retinal change can be detected from the early stages of PD, extending to the macula and peripapillary nerve fibre layer at advanced stages and showing associations with visual hallucinations and cognitive impairment.

  • Retinal imaging could provide a convenient imaging tool for early diagnosis and monitoring progression in PD, and further investigation of the link between retinal and brain pathology could provide further pathophysiological insights into neurodegenerative diseases.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Imaging of microstructural changes in the substantia nigra in PD.
Fig. 2: Retinal changes in PD.
Fig. 3: Visualizing retinal pathology in PD.
Fig. 4: Acquisition and analysis of retinal OCT images.
Fig. 5: Proposed retinal changes in PD identified by optical coherence tomography.

References

  1. Del Tredici, K. & Braak, H. Review: Sporadic Parkinson’s disease: development and distribution of α-synuclein pathology. Neuropathol. Appl. Neurobiol. 42, 33–50 (2016).

    Article  PubMed  Google Scholar 

  2. Horsager, J. et al. Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study. Brain 143, 3077–3088 (2020).

    Article  PubMed  Google Scholar 

  3. Braak, H. & Del Tredici, K. Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J. Parkinsons Dis. 7, S71–S85 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Berg, D. et al. Changing the research criteria for the diagnosis of Parkinson’s disease: obstacles and opportunities. Lancet Neurol. 12, 514–524 (2013).

    Article  PubMed  Google Scholar 

  5. London, A., Benhar, I. & Schwartz, M. The retina as a window to the brain–from eye research to CNS disorders. Nat. Rev. Neurol. 9, 44–53 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. De Groef, L. & Cordeiro, M. F. Is the eye an extension of the brain in central nervous system disease? J. Ocul. Pharmacol. Ther. 34, 129–133 (2018).

    Article  PubMed  Google Scholar 

  7. Harnois, C. & Di Paolo, T. Decreased dopamine in the retinas of patients with Parkinson’s disease. Invest. Ophthalmol. Vis. Sci. 31, 2473–2475 (1990).

    CAS  PubMed  Google Scholar 

  8. Witkovsky, P. Dopamine and retinal function. Doc. Ophthalmol. 108, 17–40 (2004).

    Article  PubMed  Google Scholar 

  9. Bodis-Wollner, I. et al. Visual dysfunction in Parkinson’s disease. Loss in spatiotemporal contrast sensitivity. Brain 110, 1675–1698 (1987).

    Article  PubMed  Google Scholar 

  10. Hutton, J. T., Morris, J. L. & Elias, J. W. Levodopa improves spatial contrast sensitivity in Parkinson’s disease. Arch. Neurol. 50, 721–724 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Lee, J. Y. et al. Retina thickness as a marker of neurodegeneration in prodromal lewy body disease. Mov. Disord. 35, 349–354 (2020).

    Article  PubMed  Google Scholar 

  12. Ortuño-Lizarán, I. et al. Dopaminergic retinal cell loss and visual dysfunction in Parkinson disease. Ann. Neurol. 88, 893–906 (2020).

    Article  PubMed  Google Scholar 

  13. Ortuño-Lizarán, I. et al. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov. Disord. 33, 1315–1324 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Baksi, S. & Singh, N. α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: implications for retinal iron dyshomeostasis in Parkinson’s disease. Sci. Rep. 7, 12843 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mammadova, N. et al. Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson’s disease. Neurobiol. Dis. 121, 1–16 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Murueta-Goyena, A. et al. Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases. Mov. Disord. 34, 1315–1324 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lee, J. Y. et al. Retinal nerve fiber layer thickness and visual hallucinations in Parkinson’s disease. Mov. Disord. 29, 61–67 (2014).

    Article  PubMed  Google Scholar 

  18. Murueta-Goyena, A. et al. Retinal thickness predicts the risk of cognitive decline in Parkinson disease. Ann. Neurol. 89, 165–176 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Ahn, J. et al. Retinal thinning associates with nigral dopaminergic loss in de novo Parkinson disease. Neurology 91, e1003–e1012 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, J. Y. et al. Macular ganglion-cell-complex layer thinning and optic nerve integrity in drug-naive Parkinson’s disease. J. Neural Transm. 126, 1695–1699 (2019).

    Article  PubMed  Google Scholar 

  21. Postuma, R. B. et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 30, 1591–1601 (2015).

    Article  PubMed  Google Scholar 

  22. Dahlstrom, A. & Fuxe, K. Localization of monoamines in the lower brain stem. Experientia 20, 398–399 (1964).

    Article  CAS  PubMed  Google Scholar 

  23. Ma, L. J. et al. Progressive changes in the retinal structure of patients with Parkinson’s disease. J. Parkinsons Dis. 8, 85–92 (2018).

    Article  PubMed  Google Scholar 

  24. Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122, 1437–1448 (1999).

    Article  PubMed  Google Scholar 

  25. Lehericy, S., Bardinet, E., Poupon, C., Vidailhet, M. & Francois, C. 7 Tesla magnetic resonance imaging: a closer look at substantia nigra anatomy in Parkinson’s disease. Mov. Disord. 29, 1574–1581 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Jellinger, K. A. Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov. Disord. 27, 8–30 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Fearnley, J. M. & Lees, A. J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991).

    Article  PubMed  Google Scholar 

  28. Carballo-Carbajal, I. et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat. Commun. 10, 973 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Beach, T. G. et al. Substantia nigra Marinesco bodies are associated with decreased striatal expression of dopaminergic markers. J. Neuropathol. Exp. Neurol. 63, 329–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Kuusisto, E., Parkkinen, L. & Alafuzoff, I. Morphogenesis of Lewy bodies: dissimilar incorporation of α-synuclein, ubiquitin, and p62. J. Neuropathol. Exp. Neurol. 62, 1241–1253 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Atkinson-Clement, C., Pinto, S., Eusebio, A. & Coulon, O. Diffusion tensor imaging in Parkinson’s disease: review and meta-analysis. Neuroimage Clin. 16, 98–110 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Loane, C. et al. Aberrant nigral diffusion in Parkinson’s disease: a longitudinal diffusion tensor imaging study. Mov. Disord. 31, 1020–1026 (2016).

    Article  PubMed  Google Scholar 

  33. Vaillancourt, D. E. et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology 72, 1378–1384 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pasternak, O., Sochen, N., Gur, Y., Intrator, N. & Assaf, Y. Free water elimination and mapping from diffusion MRI. Magn. Reson. Med. 62, 717–730 (2009).

    Article  PubMed  Google Scholar 

  35. Ofori, E. et al. Increased free water in the substantia nigra of Parkinson’s disease: a single-site and multi-site study. Neurobiol. Aging 36, 1097–1104 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Ofori, E. et al. Longitudinal changes in free-water within the substantia nigra of Parkinson’s disease. Brain 138, 2322–2331 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Burciu, R. G. et al. Progression marker of Parkinson’s disease: a 4-year multi-site imaging study. Brain 140, 2183–2192 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhou, L. et al. Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder. Brain 144, 1488–1497 (2021).

    Article  PubMed  Google Scholar 

  39. Guttuso, T. Jr. et al. Substantia nigra free water increases longitudinally in Parkinson disease. Am. J. Neuroradiol. 39, 479–484 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Arribarat, G. et al. Substantia nigra locations of iron-content, free-water and mean diffusivity abnormalities in moderate stage Parkinson’s disease. Parkinsonism Relat. Disord. 65, 146–152 (2019).

    Article  PubMed  Google Scholar 

  41. Planetta, P. J. et al. Free-water imaging in Parkinson’s disease and atypical parkinsonism. Brain 139, 495–508 (2016).

    Article  PubMed  Google Scholar 

  42. Prodoehl, J. et al. Diffusion tensor imaging of Parkinson’s disease, atypical parkinsonism, and essential tremor. Mov. Disord. 28, 1816–1822 (2013).

    Article  PubMed  Google Scholar 

  43. Andica, C. et al. Neurite orientation dispersion and density imaging of the nigrostriatal pathway in Parkinson’s disease: retrograde degeneration observed by tract-profile analysis. Parkinsonism Relat. Disord. 51, 55–60 (2018).

    Article  PubMed  Google Scholar 

  44. Kamagata, K. et al. Neurite orientation dispersion and density imaging in the substantia nigra in idiopathic Parkinson disease. Eur. Radiol. 26, 2567–2577 (2016).

    Article  PubMed  Google Scholar 

  45. Mitchell, T. et al. Neurite orientation dispersion and density imaging (NODDI) and free-water imaging in Parkinsonism. Hum. Brain Mapp. 40, 5094–5107 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Archer, D. B. et al. Development and validation of the automated imaging differentiation in parkinsonism (AID-P): a multicentre machine learning study. Lancet Digit. Health 1, e222–e231 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dexter, D. T. et al. Increased nigral iron content in postmortem parkinsonian brain. Lancet 2, 1219–1220 (1987).

    Article  CAS  PubMed  Google Scholar 

  48. Hallgren, B. & Sourander, P. The effect of age on the non-haemin iron in the human brain. J. Neurochem. 3, 41–51 (1958).

    Article  CAS  PubMed  Google Scholar 

  49. Haacke, E. M. et al. Imaging iron stores in the brain using magnetic resonance imaging. Magn. Reson. Imaging 23, 1–25 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Pietracupa, S., Martin-Bastida, A. & Piccini, P. Iron metabolism and its detection through MRI in parkinsonian disorders: a systematic review. Neurol. Sci. 38, 2095–2101 (2017).

    Article  PubMed  Google Scholar 

  51. Wang, J. Y. et al. Meta-analysis of brain iron levels of Parkinson’s disease patients determined by postmortem and MRI measurements. Sci. Rep. 6, 36669 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun, J. et al. Quantitative evaluation of iron content in idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 35, 478–485 (2020).

    Article  CAS  PubMed  Google Scholar 

  53. Langley, J. et al. Reproducible detection of nigral iron deposition in 2 Parkinson’s disease cohorts. Mov. Disord. 34, 416–419 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Langley, J., Huddleston, D. E., Sedlacik, J., Boelmans, K. & Hu, X. P. Parkinson’s disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta. Mov. Disord. 32, 441–449 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Bergsland, N. et al. Ventral posterior substantia nigra iron increases over 3 years in Parkinson’s disease. Mov. Disord. 34, 1006–1013 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Barbosa, J. H. et al. Quantifying brain iron deposition in patients with Parkinson’s disease using quantitative susceptibility mapping, R2 and R2. Magn. Reson. Imaging 33, 559–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Acosta-Cabronero, J. et al. The whole-brain pattern of magnetic susceptibility perturbations in Parkinson’s disease. Brain 140, 118–131 (2017).

    Article  PubMed  Google Scholar 

  58. Thomas, G. E. C. et al. Brain iron deposition is linked with cognitive severity in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 91, 418–425 (2020).

    Article  PubMed  Google Scholar 

  59. Ulla, M. et al. Is R2* a new MRI biomarker for the progression of Parkinson’s disease? A longitudinal follow-up. PLoS ONE 8, e57904 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wieler, M., Gee, M. & Martin, W. R. Longitudinal midbrain changes in early Parkinson’s disease: iron content estimated from R2*/MRI. Parkinsonism Relat. Disord. 21, 179–183 (2015).

    Article  PubMed  Google Scholar 

  61. Schwarz, S. T. et al. 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 9, e93814 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Schwarz, S. T. et al. Parkinson’s disease related signal change in the nigrosomes 1–5 and the substantia nigra using T2* weighted 7T MRI. Neuroimage Clin. 19, 683–689 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Kim, J. M. et al. Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Parkinsonism Relat. Disord. 26, 47–54 (2016).

    Article  CAS  PubMed  Google Scholar 

  64. Bae, Y. J. et al. Loss of substantia nigra hyperintensity at 3.0-T MR imaging in idiopathic REM sleep behavior disorder: comparison with (123)I-FP-CIT SPECT. Radiology 287, 285–293 (2018).

    Article  PubMed  Google Scholar 

  65. De Marzi, R. et al. Loss of dorsolateral nigral hyperintensity on 3.0 tesla susceptibility-weighted imaging in idiopathic rapid eye movement sleep behavior disorder. Ann. Neurol. 79, 1026–1030 (2016).

    Article  PubMed  Google Scholar 

  66. Frosini, D. et al. Seven tesla MRI of the substantia nigra in patients with rapid eye movement sleep behavior disorder. Parkinsonism Relat. Disord. 43, 105–109 (2017).

    Article  PubMed  Google Scholar 

  67. Reiter, E. et al. Dorsolateral nigral hyperintensity on 3.0T susceptibility-weighted imaging in neurodegenerative Parkinsonism. Mov. Disord. 30, 1068–1076 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Bae, Y. J. et al. Loss of nigral hyperintensity on 3 Tesla MRI of parkinsonism: comparison with (123)I-FP-CIT SPECT. Mov. Disord. 31, 684–692 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. An, H. et al. Quantifying iron deposition within the substantia nigra of Parkinson’s disease by quantitative susceptibility mapping. J. Neurol. Sci. 386, 46–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  70. Bae, Y. J. et al. Comparison of susceptibility-weighted imaging and susceptibility map-weighted imaging for the diagnosis of Parkinsonism with nigral hyperintensity. Eur. J. Radiol. 134, 109398 (2021).

    Article  PubMed  Google Scholar 

  71. Cheng, Z. et al. Imaging the nigrosome 1 in the substantia nigra using susceptibility weighted imaging and quantitative susceptibility mapping: an application to Parkinson’s disease. Neuroimage Clin. 25, 102103 (2020).

    Article  PubMed  Google Scholar 

  72. Nam, Y., Gho, S. M., Kim, D. H., Kim, E. Y. & Lee, J. Imaging of nigrosome 1 in substantia nigra at 3T using multiecho susceptibility map-weighted imaging (SMWI). J. Magn. Reson. Imaging 46, 528–536 (2017).

    Article  PubMed  Google Scholar 

  73. Kim, E. Y. et al. Diagnosis of early-stage idiopathic Parkinson’s disease using high-resolution quantitative susceptibility mapping combined with histogram analysis in the substantia nigra at 3 T. J. Clin. Neurol. 14, 90–97 (2018).

    Article  PubMed  Google Scholar 

  74. Barber, T. R. et al. Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline. Ann. Clin. Transl. Neurol. 7, 26–35 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Reimao, S., Guerreiro, C., Seppi, K., Ferreira, J. J. & Poewe, W. A standardized MR imaging protocol for parkinsonism. Mov. Disord. 35, 1745–1750 (2020).

    Article  PubMed  Google Scholar 

  76. Fedorow, H. et al. Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson’s disease. Prog. Neurobiol. 75, 109–124 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Sulzer, D. et al. Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. Proc. Natl Acad. Sci. USA 97, 11869–11874 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zecca, L. et al. Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J. Neurochem. 106, 1866–1875 (2008).

    CAS  PubMed  Google Scholar 

  79. Zhang, W. et al. Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson’s disease. Neurotox. Res. 19, 63–72 (2011).

    Article  PubMed  Google Scholar 

  80. Sulzer, D. et al. Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease. npj Parkinson’s Dis. 4, 11 (2018).

    Article  Google Scholar 

  81. Chen, X. et al. Simultaneous imaging of locus coeruleus and substantia nigra with a quantitative neuromelanin MRI approach. Magn. Reson. Imaging 32, 1301–1306 (2014).

    Article  PubMed  Google Scholar 

  82. Schwarz, S. T. et al. T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson’s disease. Mov. Disord. 26, 1633–1638 (2011).

    Article  PubMed  Google Scholar 

  83. Ohtsuka, C. et al. Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson’s disease using neuromelanin-sensitive MR imaging. Neurosci. Lett. 541, 93–98 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Fabbri, M. et al. Substantia nigra neuromelanin as an imaging biomarker of disease progression in Parkinson’s disease. J. Parkinsons Dis. 7, 491–501 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Reimao, S. et al. Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson’s disease patients. Eur. J. Neurol. 22, 540–546 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, J. et al. Neuromelanin-sensitive magnetic resonance imaging features of the substantia nigra and locus coeruleus in de novo Parkinson’s disease and its phenotypes. Eur. J. Neurol. 25, 949-e73 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Matsuura, K. et al. Neuromelanin magnetic resonance imaging in Parkinson’s disease and multiple system atrophy. Eur. Neurol. 70, 70–77 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Ohtsuka, C. et al. Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. Parkinsonism Relat. Disord. 20, 755–760 (2014).

    Article  PubMed  Google Scholar 

  89. Schwarz, S. T., Xing, Y., Tomar, P., Bajaj, N. & Auer, D. P. In vivo assessment of brainstem depigmentation in Parkinson disease: potential as a severity marker for multicenter studies. Radiology 283, 789–798 (2017).

    Article  PubMed  Google Scholar 

  90. Biondetti, E. et al. Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease. Brain 143, 2757–2770 (2020).

    Article  PubMed  Google Scholar 

  91. Gaurav, R. et al. Longitudinal changes in neuromelanin MRI signal in Parkinson’s disease: a progression marker. Mov. Disord. 36, 1592–1602 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Matsuura, K. et al. A longitudinal study of neuromelanin-sensitive magnetic resonance imaging in Parkinson’s disease. Neurosci. Lett. 633, 112–117 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Garcia-Lorenzo, D. et al. The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease. Brain 136, 2120–2129 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Ehrminger, M. et al. The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder. Brain 139, 1180–1188 (2016).

    Article  PubMed  Google Scholar 

  95. Knudsen, K. et al. In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet Neurol. 17, 618–628 (2018).

    Article  PubMed  Google Scholar 

  96. Pyatigorskaya, N. et al. Magnetic resonance imaging biomarkers to assess substantia nigra damage in idiopathic rapid eye movement sleep behavior disorder. Sleep 40, zsx149 (2017).

    Article  Google Scholar 

  97. Langley, J. et al. Diffusion tensor imaging of the substantia nigra in Parkinson’s disease revisited. Hum. Brain Mapp. 37, 2547–2556 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Safai, A. et al. Microstructural abnormalities of substantia nigra in Parkinson’s disease: a neuromelanin sensitive MRI atlas based study. Hum. Brain Mapp. 41, 1323–1333 (2020).

    Article  PubMed  Google Scholar 

  99. He, N. et al. Imaging iron and neuromelanin simultaneously using a single 3D gradient echo magnetization transfer sequence: combining neuromelanin, iron and the nigrosome-1 sign as complementary imaging biomarkers in early stage Parkinson’s disease. Neuroimage 230, 117810 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Perez Akly, M. S. et al. Accuracy of nigrosome-1 detection to discriminate patients with Parkinson’s disease and essential tremor. Neuroradiol. J. 32, 395–400 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wang, J. et al. Neuromelanin-sensitive MRI of the substantia nigra: an imaging biomarker to differentiate essential tremor from tremor-dominant Parkinson’s disease. Parkinsonism Relat. Disord. 58, 3–8 (2019).

    Article  PubMed  Google Scholar 

  102. Jin, L. et al. Combined visualization of nigrosome-1 and neuromelanin in the substantia nigra using 3T MRI for the differential diagnosis of essential tremor and de novo Parkinson’s disease. Front. Neurol. 10, 100 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Nandhagopal, R. et al. Longitudinal evolution of compensatory changes in striatal dopamine processing in Parkinson’s disease. Brain 134, 3290–3298 (2011).

    Article  PubMed  Google Scholar 

  104. de la Fuente-Fernandez, R. et al. Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease. Ann. Neurol. 69, 803–810 (2011).

    Article  PubMed  Google Scholar 

  105. Shin, J. H. et al. Longitudinal change in dopamine transporter availability in idiopathic REM sleep behavior disorder. Neurology 95, e3081–e3092 (2020).

    Article  CAS  PubMed  Google Scholar 

  106. Iranzo, A. et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol. 10, 797–805 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Seibyl, J. & Cheng, D. Four year longitudinal assessment of DAT imaging biomarkers in a progressing Parkinson disease cohort: analysis strategies and implications for treatment trial design [abstract]. J. Nucl. Med. 59 (Suppl. 1), 628 (2018).

    Google Scholar 

  108. Iranzo, A. et al. Dopamine transporter imaging deficit predicts early transition to synucleinopathy in idiopathic rapid eye movement sleep behavior disorder. Ann. Neurol. 82, 419–428 (2017).

    Article  CAS  PubMed  Google Scholar 

  109. Jennings, D. et al. Conversion to Parkinson disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 74, 933–940 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Lenfeldt, N., Eriksson, J., Astrom, B., Forsgren, L. & Mo, S. J. Fractional anisotropy and mean diffusion as measures of dopaminergic function in Parkinson’s disease: challenging results. J. Parkinsons Dis. 7, 129–142 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Isaias, I. U. et al. Neuromelanin imaging and dopaminergic loss in Parkinson’s disease. Front. Aging Neurosci. 8, 196 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Kuya, K. et al. Evaluation of Parkinson’s disease by neuromelanin-sensitive magnetic resonance imaging and (123)I-FP-CIT SPECT. Acta Radiol. 59, 593–598 (2018).

    Article  PubMed  Google Scholar 

  113. Martin-Bastida, A. et al. Relationship between neuromelanin and dopamine terminals within the Parkinson’s nigrostriatal system. Brain 142, 2023–2036 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Saari, L. et al. Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease. Neurology 88, 1461–1467 (2017).

    Article  CAS  PubMed  Google Scholar 

  115. Karimi, M. et al. Validation of nigrostriatal positron emission tomography measures: critical limits. Ann. Neurol. 73, 390–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136, 2419–2431 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Biondetti, E. et al. The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease. Brain 144, 3114–3125 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Tatton, W. G., Kwan, M. M., Verrier, M. C., Seniuk, N. A. & Theriault, E. MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells. Brain Res. 527, 21–31 (1990).

    Article  CAS  PubMed  Google Scholar 

  119. Meng, T., Zheng, Z. H., Liu, T. T. & Lin, L. Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat. Neurochem. Res. 37, 1050–1056 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Esteve-Rudd, J. et al. Rotenone induces degeneration of photoreceptors and impairs the dopaminergic system in the rat retina. Neurobiol. Dis. 44, 102–115 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Kolb, H., Cuenca, N., Wang, H. H. & Dekorver, L. The synaptic organization of the dopaminergic amacrine cell in the cat retina. J. Neurocytol. 19, 343–366 (1990).

    Article  CAS  PubMed  Google Scholar 

  122. Popova, E. The role of dopamine in retinal function. Webvision https://webvision.med.utah.edu/book/part-iv-neurotransmitters-in-the-retina-2/the-role-of-dopamine-in-retinal-function-by-elka-popova/ (2021).

  123. Bodis-Wollner, I. & Yahr, M. D. Measurements of visual evoked potentials in Parkinson’s disease. Brain 101, 661–671 (1978).

    Article  CAS  PubMed  Google Scholar 

  124. Jeon, B. S., Lee, K. W., Lee, S. B. & Myung, H. J. Flash ERG findings in Parkinson’s disease. J. Korean Neurol. Assoc. 5, 7 (1987).

    Google Scholar 

  125. Garcia-Martin, E. et al. Electrophysiology and optical coherence tomography to evaluate Parkinson disease severity. Invest. Ophthalmol. Vis. Sci. 55, 696–705 (2014).

    Article  PubMed  Google Scholar 

  126. Langheinrich, T. et al. Visual contrast response functions in Parkinson’s disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin. Neurophysiol. 111, 66–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Moschos, M. M. et al. Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. Eur. J. Ophthalmol. 21, 24–29 (2011).

    Article  PubMed  Google Scholar 

  128. Peppe, A. et al. Low contrast stimuli enhance PERG sensitivity to the visual dysfunction in Parkinson’s disease. Electroencephalogr. Clin. Neurophysiol. 82, 453–457 (1992).

    Article  CAS  PubMed  Google Scholar 

  129. Tagliati, M., Bodis-Wollner, I. & Yahr, M. D. The pattern electroretinogram in Parkinson’s disease reveals lack of retinal spatial tuning. Electroencephalogr. Clin. Neurophysiol. 100, 1–11 (1996).

    Article  CAS  PubMed  Google Scholar 

  130. Stanzione, P. et al. Pattern visual evoked potentials and electroretinogram abnormalities in Parkinson’s disease: effects of L-dopa therapy. Clin. Vis. Sci. 4, 115–127 (1989).

    Google Scholar 

  131. Bodis-Wollner, I. & Tzelepi, A. The push-pull action of dopamine on spatial tuning of the monkey retina: the effects of dopaminergic deficiency and selective D1 and D2 receptor ligands on the pattern electroretinogram. Vis. Res. 38, 1479–1487 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. Bulens, C., Meerwaldt, J. D., van der Wildt, G. J. & Keemink, C. J. Visual contrast sensitivity in drug-induced parkinsonism. J. Neurol. Neurosurg. Psychiatry 52, 341–345 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bodis-Wollner, I. Foveal vision is impaired in Parkinson’s disease. Parkinsonism Relat. Disord. 19, 1–14 (2013).

    Article  PubMed  Google Scholar 

  134. Diederich, N. J., Raman, R., Leurgans, S. & Goetz, C. G. Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch. Neurol. 59, 1249–1252 (2002).

    Article  PubMed  Google Scholar 

  135. Silva, M. F. et al. Independent patterns of damage within magno-, parvo- and koniocellular pathways in Parkinson’s disease. Brain 128, 2260–2271 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Hasanov, S. et al. Functional and morphological assessment of ocular structures and follow-up of patients with early-stage Parkinson’s disease. Int. Ophthalmol. 39, 1255–1262 (2019).

    Article  PubMed  Google Scholar 

  137. Matar, E., Phillips, J. R., Martens, K. A. E., Halliday, G. M. & Lewis, S. J. G. Impaired color discrimination–a specific marker of hallucinations in Lewy body disorders. J. Geriatr. Psychiatry Neurol. 32, 257–264 (2019).

    Article  PubMed  Google Scholar 

  138. Bertrand, J. A. et al. Color discrimination deficits in Parkinson’s disease are related to cognitive impairment and white-matter alterations. Mov. Disord. 27, 1781–1788 (2012).

    Article  PubMed  Google Scholar 

  139. Kertelge, L. et al. Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson’s disease. Mov. Disord. 25, 2665–2669 (2010).

    Article  PubMed  Google Scholar 

  140. Oh, Y. S. et al. Color vision in Parkinson’s disease and essential tremor. Eur. J. Neurol. 18, 577–583 (2011).

    Article  PubMed  Google Scholar 

  141. Polo, V. et al. Visual dysfunction and its correlation with retinal changes in patients with Parkinson’s disease: an observational cross-sectional study. BMJ Open 6, e009658 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Sartucci, F. & Porciatti, V. Visual-evoked potentials to onset of chromatic red-green and blue-yellow gratings in Parkinson’s disease never treated with L-dopa. J. Clin. Neurophysiol. 23, 431–435 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Stenc Bradvica, I., Bradvica, M., Matic, S. & Reisz-Majic, P. Visual dysfunction in patients with Parkinson’s disease and essential tremor. Neurol. Sci. 36, 257–262 (2015).

    Article  PubMed  Google Scholar 

  144. Buttner, T., Kuhn, W. & Przuntek, H. Alterations in chromatic contour perception in de novo parkinsonian patients. Eur. Neurol. 35, 226–229 (1995).

    Article  CAS  PubMed  Google Scholar 

  145. Fereshtehnejad, S. M. et al. New clinical subtypes of Parkinson disease and their longitudinal progression: a prospective cohort comparison with other phenotypes. JAMA Neurol. 72, 863–873 (2015).

    Article  PubMed  Google Scholar 

  146. Haug, B. A., Kolle, R. U., Trenkwalder, C., Oertel, W. H. & Paulus, W. Predominant affection of the blue cone pathway in Parkinson’s disease. Brain 118, 771–778 (1995).

    Article  PubMed  Google Scholar 

  147. Muller, T. et al. Colour vision abnormalities do not correlate with dopaminergic nigrostriatal degeneration in Parkinson’s disease. J. Neurol. 245, 659–664 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Muller, T., Kuhn, W., Buttner, T. & Przuntek, H. Colour vision abnormalities and movement time in Parkinson’s disease. Eur. J. Neurol. 6, 711–715 (1999).

    Article  CAS  PubMed  Google Scholar 

  149. Pieri, V., Diederich, N. J., Raman, R. & Goetz, C. G. Decreased color discrimination and contrast sensitivity in Parkinson’s disease. J. Neurol. Sci. 172, 7–11 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Postuma, R. B., Gagnon, J. F., Vendette, M., Charland, K. & Montplaisir, J. Manifestations of Parkinson disease differ in association with REM sleep behavior disorder. Mov. Disord. 23, 1665–1672 (2008).

    Article  PubMed  Google Scholar 

  151. Price, M. J., Feldman, R. G., Adelberg, D. & Kayne, H. Abnormalities in color vision and contrast sensitivity in Parkinson’s disease. Neurology 42, 887–890 (1992).

    Article  CAS  PubMed  Google Scholar 

  152. Regan, B. C., Freudenthaler, N., Kolle, R., Mollon, J. D. & Paulus, W. Colour discrimination thresholds in Parkinson’s disease: results obtained with a rapid computer-controlled colour vision test. Vis. Res. 38, 3427–3431 (1998).

    Article  CAS  PubMed  Google Scholar 

  153. Satue, M. et al. Evaluation of progressive visual dysfunction and retinal degeneration in patients with Parkinson’s disease. Invest. Ophthalmol. Vis. Sci. 58, 1151–1157 (2017).

    Article  PubMed  Google Scholar 

  154. Barbato, L., Rinalduzzi, S., Laurenti, M., Ruggieri, S. & Accornero, N. Color VEPs in Parkinson’s disease. Electroencephalogr. Clin. Neurophysiol. 92, 169–172 (1994).

    Article  CAS  PubMed  Google Scholar 

  155. Birch, J., Kolle, R. U., Kunkel, M., Paulus, W. & Upadhyay, P. Acquired colour deficiency in patients with Parkinson’s disease. Vis. Res. 38, 3421–3426 (1998).

    Article  CAS  PubMed  Google Scholar 

  156. Jones, R. D., Donaldson, I. M. & Timmings, P. L. Impairment of high-contrast visual acuity in Parkinson’s disease. Mov. Disord. 7, 232–238 (1992).

    Article  CAS  PubMed  Google Scholar 

  157. Lin, T. P. et al. Abnormal visual contrast acuity in Parkinson’s disease. J. Parkinsons Dis. 5, 125–130 (2015).

    Article  PubMed  Google Scholar 

  158. Gupta, H. V. et al. Contrast acuity with different colors in Parkinson’s disease. Mov. Disord. Clin. Pract. 6, 672–677 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Regan, D. & Neima, D. Low-contrast letter charts in early diabetic retinopathy, ocular hypertension, glaucoma, and Parkinson’s disease. Br. J. Ophthalmol. 68, 885–889 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Rascol, O. et al. Abnormal ocular movements in Parkinson’s disease. Evidence for involvement of dopaminergic systems. Brain 112, 1193–1214 (1989).

    Article  PubMed  Google Scholar 

  161. Terao, Y. et al. Initiation and inhibitory control of saccades with the progression of Parkinson’s disease–changes in three major drives converging on the superior colliculus. Neuropsychologia 49, 1794–1806 (2011).

    Article  PubMed  Google Scholar 

  162. Marino, S., Lanzafame, P., Sessa, E., Bramanti, A. & Bramanti, P. The effect of L-Dopa administration on pursuit ocular movements in suspected Parkinson’s disease. Neurol. Sci. 31, 381–385 (2010).

    Article  PubMed  Google Scholar 

  163. Stock, L., Kruger-Zechlin, C., Deeb, Z., Timmermann, L. & Waldthaler, J. Natural reading in Parkinson’s disease with and without mild cognitive impairment. Front. Aging Neurosci. 12, 120 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Moro, E. et al. Visual dysfunction of the superior colliculus in de novo parkinsonian patients. Ann. Neurol. 87, 533–546 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Archibald, N. K., Clarke, M. P., Mosimann, U. P. & Burn, D. J. The retina in Parkinson’s disease. Brain 132, 1128–1145 (2009).

    Article  PubMed  Google Scholar 

  166. Davidsdottir, S., Cronin-Golomb, A. & Lee, A. Visual and spatial symptoms in Parkinson’s disease. Vis. Res. 45, 1285–1296 (2005).

    Article  PubMed  Google Scholar 

  167. Pagonabarraga, J. et al. Minor hallucinations occur in drug-naive Parkinson’s disease patients, even from the premotor phase. Mov. Disord. 31, 45–52 (2016).

    Article  PubMed  Google Scholar 

  168. Bradley, V. A., Welch, J. L. & Dick, D. J. Visuospatial working memory in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 52, 1228–1235 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fernandez-Baizan, C. et al. Patients with Parkinson’s disease show alteration in their visuospatial abilities and in their egocentric and allocentric spatial orientation measured by card placing tests. J. Parkinsons Dis. 10, 1807–1816 (2020).

    Article  PubMed  Google Scholar 

  170. Lee, J. J. et al. Optic nerve integrity as a visuospatial cognitive predictor in Parkinson’s disease. Parkinsonism Relat. Disord. 31, 41–45 (2016).

    Article  PubMed  Google Scholar 

  171. Bodis-Wollner, I., Kozlowski, P. B., Glazman, S. & Miri, S. α-synuclein in the inner retina in parkinson disease. Ann. Neurol. 75, 964–966 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Beach, T. G. et al. Phosphorylated α-synuclein-immunoreactive retinal neuronal elements in Parkinson’s disease subjects. Neurosci. Lett. 571, 34–38 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cuenca, N. et al. Morphological impairments in retinal neurons of the scotopic visual pathway in a monkey model of Parkinson’s disease. J. Comp. Neurol. 493, 261–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  174. Deans, M. R., Volgyi, B., Goodenough, D. A., Bloomfield, S. A. & Paul, D. L. Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina. Neuron 36, 703–712 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Benarroch, E. E. The melanopsin system: phototransduction, projections, functions, and clinical implications. Neurology 76, 1422–1427 (2011).

    Article  PubMed  Google Scholar 

  176. Fifel, K. & Videnovic, A. Light therapy in Parkinson’s disease: towards mechanism-based protocols. Trends Neurosci. 41, 252–254 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Esquiva, G., Lax, P., Perez-Santonja, J. J., Garcia-Fernandez, J. M. & Cuenca, N. Loss of melanopsin-expressing ganglion cell subtypes and dendritic degeneration in the aging human retina. Front. Aging Neurosci. 9, 79 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Ortuño-Lizarán, I. et al. Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson’s disease. Acta Neuropathol. Commun. 6, 90 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Nguyen-Legros, J. & Hicks, D. Renewal of photoreceptor outer segments and their phagocytosis by the retinal pigment epithelium. Int. Rev. Cytol. 196, 245–313 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. Gabriele, M. L. et al. Optical coherence tomography: history, current status, and laboratory work. Invest. Ophthalmol. Vis. Sci. 52, 2425–2436 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Fujimoto, J. & Swanson, E. The development, commercialization, and impact of optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 57, OCT1–OCT13 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Cruz-Herranz, A. et al. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology 86, 2303–2309 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Aytulun, A. et al. APOSTEL 2.0 recommendations for reporting quantitative optical coherence tomography studies. Neurology 97, 68–79 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Altintas, O., Iseri, P., Ozkan, B. & Caglar, Y. Correlation between retinal morphological and functional findings and clinical severity in Parkinson’s disease. Doc. Ophthalmol. 116, 137–146 (2008).

    Article  PubMed  Google Scholar 

  185. Aydin, T. S. et al. Optical coherence tomography findings in Parkinson’s disease. Kaohsiung J. Med. Sci. 34, 166–171 (2018).

    Article  PubMed  Google Scholar 

  186. Eraslan, M. et al. Comparison of optical coherence tomography findings in patients with primary open-angle glaucoma and Parkinson disease. J. Glaucoma 25, e639–e646 (2016).

    Article  PubMed  Google Scholar 

  187. Jimenez, B., Ascaso, F. J., Cristobal, J. A. & Lopez del Val, J. Development of a prediction formula of Parkinson disease severity by optical coherence tomography. Mov. Disord. 29, 68–74 (2014).

    Article  PubMed  Google Scholar 

  188. Kaur, M. et al. Correlation between structural and functional retinal changes in Parkinson disease. J. Neuroophthalmol. 35, 254–258 (2015).

    Article  PubMed  Google Scholar 

  189. Moschos, M. M. & Chatziralli, I. P. Evaluation of choroidal and retinal thickness changes in Parkinson’s disease using spectral domain optical coherence tomography. Semin. Ophthalmol. 33, 494–497 (2018).

    Article  PubMed  Google Scholar 

  190. Pilat, A. et al. In vivo morphology of the optic nerve and retina in patients with Parkinson’s disease. Invest. Ophthalmol. Vis. Sci. 57, 4420–4427 (2016).

    Article  PubMed  Google Scholar 

  191. Satue, M. et al. Use of Fourier-domain OCT to detect retinal nerve fiber layer degeneration in Parkinson’s disease patients. Eye 27, 507–514 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Satue, M. et al. Retinal thinning and correlation with functional disability in patients with Parkinson’s disease. Br. J. Ophthalmol. 98, 350–355 (2014).

    Article  CAS  PubMed  Google Scholar 

  193. Sengupta, P. et al. Optical coherence tomography findings in patients of Parkinson’s disease: an Indian perspective. Ann. Indian Acad. Neurol. 21, 150–155 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Kirbas, S., Turkyilmaz, K., Tufekci, A. & Durmus, M. Retinal nerve fiber layer thickness in Parkinson disease. J. Neuroophthalmol. 33, 62–65 (2013).

    Article  PubMed  Google Scholar 

  195. La Morgia, C. et al. Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern? Eur. J. Neurol. 20, 198–201 (2013).

    Article  PubMed  Google Scholar 

  196. Moreno-Ramos, T., Benito-Leon, J., Villarejo, A. & Bermejo-Pareja, F. Retinal nerve fiber layer thinning in dementia associated with Parkinson’s disease, dementia with Lewy bodies, and Alzheimer’s disease. J. Alzheimers Dis. 34, 659–664 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Ucak, T. et al. Analysis of the retinal nerve fiber and ganglion cell–inner plexiform layer by optical coherence tomography in Parkinson’s patients. Parkinsonism Relat. Disord. 31, 59–64 (2016).

    Article  PubMed  Google Scholar 

  198. Rohani, M. et al. Retinal nerve changes in patients with tremor dominant and akinetic rigid Parkinson’s disease. Neurol. Sci. 34, 689–693 (2013).

    Article  PubMed  Google Scholar 

  199. Sung, M. S. et al. Inner retinal thinning as a biomarker for cognitive impairment in de novo Parkinson’s disease. Sci. Rep. 9, 11832 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Garcia-Martin, E. et al. Ability and reproducibility of Fourier-domain optical coherence tomography to detect retinal nerve fiber layer atrophy in Parkinson’s disease. Ophthalmology 119, 2161–2167 (2012).

    Article  PubMed  Google Scholar 

  201. Roth, N. M. et al. Photoreceptor layer thinning in idiopathic Parkinson’s disease. Mov. Disord. 29, 1163–1170 (2014).

    Article  PubMed  Google Scholar 

  202. Aaker, G. D. et al. Detection of retinal changes in Parkinson’s disease with spectral-domain optical coherence tomography. Clin. Ophthalmol. 4, 1427–1432 (2010).

    PubMed  PubMed Central  Google Scholar 

  203. Albrecht, P. et al. Optical coherence tomography in parkinsonian syndromes. PLoS ONE 7, e34891 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Archibald, N. K., Clarke, M. P., Mosimann, U. P. & Burn, D. J. Retinal thickness in Parkinson’s disease. Parkinsonism Relat. Disord. 17, 431–436 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Bittersohl, D. et al. Detection of retinal changes in idiopathic Parkinson’s disease using high-resolution optical coherence tomography and Heidelberg retina tomography. Acta Ophthalmol. 93, e578–e584 (2015).

    Article  PubMed  Google Scholar 

  206. Chorostecki, J. et al. Characterization of retinal architecture in Parkinson’s disease. J. Neurol. Sci. 355, 44–48 (2015).

    Article  PubMed  Google Scholar 

  207. Mailankody, P. et al. Optical coherence tomography as a tool to evaluate retinal changes in Parkinson’s disease. Parkinsonism Relat. Disord. 21, 1164–1169 (2015).

    Article  PubMed  Google Scholar 

  208. Nowacka, B., Lubinski, W., Honczarenko, K., Potemkowski, A. & Safranow, K. Bioelectrical function and structural assessment of the retina in patients with early stages of Parkinson’s disease (PD). Doc. Ophthalmol. 131, 95–104 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Quagliato, L. B., Domingues, C., Quagliato, E. M., Abreu, E. B. & Kara-Junior, N. Applications of visual evoked potentials and Fourier-domain optical coherence tomography in Parkinson’s disease: a controlled study. Arq. Bras. Oftalmol. 77, 238–242 (2014).

    Article  PubMed  Google Scholar 

  210. Tugcu, B. et al. Evaluation of retinal alterations in Parkinson disease and tremor diseases. Acta Neurol. Belg. 120, 107–113 (2020).

    Article  PubMed  Google Scholar 

  211. Yang, Z. J. et al. Retinal nerve fiber layer thinning: a window into rapid eye movement sleep behavior disorders in Parkinson’s disease. Sleep. Breath. 20, 1285–1292 (2016).

    Article  PubMed  Google Scholar 

  212. Bayhan, H. A., Aslan Bayhan, S., Tanik, N. & Gurdal, C. The association of spectral-domain optical coherence tomography determined ganglion cell complex parameters and disease severity in Parkinson’s disease. Curr. Eye Res. 39, 1117–1122 (2014).

    Article  CAS  PubMed  Google Scholar 

  213. Garcia-Martin, E. et al. Distribution of retinal layer atrophy in patients with Parkinson disease and association with disease severity and duration. Am. J. Ophthalmol. 157, 470–478.e2 (2014).

    Article  PubMed  Google Scholar 

  214. Hajee, M. E. et al. Inner retinal layer thinning in Parkinson disease. Arch. Ophthalmol. 127, 737–741 (2009).

    Article  PubMed  Google Scholar 

  215. Unlu, M., Gulmez Sevim, D., Gultekin, M. & Karaca, C. Correlations among multifocal electroretinography and optical coherence tomography findings in patients with Parkinson’s disease. Neurol. Sci. 39, 533–541 (2018).

    Article  PubMed  Google Scholar 

  216. Zivkovic, M. et al. Retinal ganglion cell/inner plexiform layer thickness in patients with Parkinson’s disease. Folia Neuropathol. 55, 168–173 (2017).

    Article  PubMed  Google Scholar 

  217. Chrysou, A., Jansonius, N. M. & van Laar, T. Retinal layers in Parkinson’s disease: a meta-analysis of spectral-domain optical coherence tomography studies. Parkinsonism Relat. Disord. 64, 40–49 (2019).

    Article  PubMed  Google Scholar 

  218. Visser, F. et al. Visual hallucinations in Parkinson’s disease are associated with thinning of the inner retina. Sci. Rep. 10, 21110 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Sari, E. S., Koc, R., Yazici, A., Sahin, G. & Ermis, S. S. Ganglion cell-inner plexiform layer thickness in patients with Parkinson disease and association with disease severity and duration. J. Neuroophthalmol. 35, 117–121 (2015).

    Article  PubMed  Google Scholar 

  220. Cubo, E. et al. Lack of association of morphologic and functional retinal changes with motor and non-motor symptoms severity in Parkinson’s disease. J. Neural Transm. 121, 139–145 (2014).

    Article  PubMed  Google Scholar 

  221. Matlach, J. et al. Retinal changes in Parkinson’s disease and glaucoma. Parkinsonism Relat. Disord. 56, 41–46 (2018).

    Article  PubMed  Google Scholar 

  222. Schneider, M. et al. Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study. J. Neural Transm. 121, 41–47 (2014).

    Article  PubMed  Google Scholar 

  223. Miri, S., Glazman, S., Mylin, L. & Bodis-Wollner, I. A combination of retinal morphology and visual electrophysiology testing increases diagnostic yield in Parkinson’s disease. Parkinsonism Relat. Disord. 22 (Suppl. 1), S134–S137 (2016).

    Article  PubMed  Google Scholar 

  224. Zhang, J. R. et al. Correlations between retinal nerve fiber layer thickness and cognitive progression in Parkinson’s disease: a longitudinal study. Parkinsonism Relat. Disord. 82, 92–97 (2021).

    Article  PubMed  Google Scholar 

  225. Savy, C., Simon, A. & Nguyen-Legros, J. Spatial geometry of the dopamine innervation in the avascular area of the human fovea. Vis. Neurosci. 7, 487–498 (1991).

    Article  CAS  PubMed  Google Scholar 

  226. Djamgoz, M. B., Hankins, M. W., Hirano, J. & Archer, S. N. Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vis. Res. 37, 3509–3529 (1997).

    Article  CAS  PubMed  Google Scholar 

  227. Nir, I. & Iuvone, P. M. Alterations in light-evoked dopamine metabolism in dystrophic retinas of mutant rds mice. Brain Res. 649, 85–94 (1994).

    Article  CAS  PubMed  Google Scholar 

  228. Miri, S. et al. The avascular zone and neuronal remodeling of the fovea in Parkinson disease. Ann. Clin. Transl. Neurol. 2, 196–201 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Curcio, C. A. & Allen, K. A. Topography of ganglion cells in human retina. J. Comp. Neurol. 300, 5–25 (1990).

    Article  CAS  PubMed  Google Scholar 

  230. Lee, J. Y., Ahn, J., Shin, J. Y. & Jeon, B. Parafoveal change and dopamine loss in the retina with Parkinson’s disease. Ann. Neurol. 89, 421–422 (2021).

    Article  PubMed  Google Scholar 

  231. Faucheux, B. A., Bonnet, A. M., Agid, Y. & Hirsch, E. C. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 353, 981–982 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Froger, N. et al. VEGF is an autocrine/paracrine neuroprotective factor for injured retinal ganglion neurons. Sci. Rep. 10, 12409 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Desai Bradaric, B., Patel, A., Schneider, J. A., Carvey, P. M. & Hendey, B. Evidence for angiogenesis in Parkinson’s disease, incidental Lewy body disease, and progressive supranuclear palsy. J. Neural Transm. 119, 59–71 (2012).

    Article  PubMed  Google Scholar 

  234. Wada, K. et al. Expression levels of vascular endothelial growth factor and its receptors in Parkinson’s disease. Neuroreport 17, 705–709 (2006).

    Article  CAS  PubMed  Google Scholar 

  235. Yasuda, T. et al. Correlation between levels of pigment epithelium-derived factor and vascular endothelial growth factor in the striatum of patients with Parkinson’s disease. Exp. Neurol. 206, 308–317 (2007).

    Article  CAS  PubMed  Google Scholar 

  236. Lee, J. Y. et al. Lateral geniculate atrophy in Parkinson’s with visual hallucination: a trans-synaptic degeneration? Mov. Disord. 31, 547–554 (2016).

    Article  PubMed  Google Scholar 

  237. Oxtoby, N. P. et al. Sequence of clinical and neurodegeneration events in Parkinson’s disease progression. Brain 144, 975–988 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Williams-Gray, C. H., Foltynie, T., Brayne, C. E., Robbins, T. W. & Barker, R. A. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 130, 1787–1798 (2007).

    Article  CAS  PubMed  Google Scholar 

  239. Zarkali, A., McColgan, P., Leyland, L. A., Lees, A. J. & Weil, R. S. Visual dysfunction predicts cognitive impairment and white matter degeneration in Parkinson’s disease. Mov. Disord. 36, 1191–1202 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Leyland, L. A. et al. Visual tests predict dementia risk in Parkinson disease. Neurol. Clin. Pract. 10, 29–39 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Hong, S. B. et al. Contrast sensitivity impairment in drug-naive Parkinson’s disease patients associates with early cognitive decline. Neurol. Sci. 41, 1837–1842 (2020).

    Article  PubMed  Google Scholar 

  242. Akyol, E., Hagag, A. M., Sivaprasad, S. & Lotery, A. J. Adaptive optics: principles and applications in ophthalmology. Eye 35, 244–264 (2021).

    Article  PubMed  Google Scholar 

  243. Dong, Z. M., Wollstein, G., Wang, B. & Schuman, J. S. Adaptive optics optical coherence tomography in glaucoma. Prog. Retin. Eye Res. 57, 76–88 (2017).

    Article  PubMed  Google Scholar 

  244. Robbins, C. B. et al. Characterization of retinal microvascular and choroidal structural changes in Parkinson disease. JAMA Ophthalmol. 139, 182–188 (2021).

    Article  PubMed  Google Scholar 

  245. Zou, J. et al. Combination of optical coherence tomography (OCT) and OCT angiography increases diagnostic efficacy of Parkinson’s disease. Quant. Imaging Med. Surg. 10, 1930–1939 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Koronyo, Y. et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight 2, e93621 (2017).

    Article  PubMed Central  Google Scholar 

  247. Yap, T. E., Donna, P., Almonte, M. T. & Cordeiro, M. F. Real-time imaging of retinal ganglion cell apoptosis. Cells 7, 60 (2018).

    Article  PubMed Central  Google Scholar 

  248. Cordeiro, M. F. et al. Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc. Natl Acad. Sci. USA 101, 13352–13356 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Cordeiro, M. F. et al. Real-time imaging of single neuronal cell apoptosis in patients with glaucoma. Brain 140, 1757–1767 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

J.-Y.L., A.M.-B., A.M.-G. and N.C. researched data for the article. J.-Y.L., I.G., P.P. and B.J. contributed substantially to discussion of the content. J.-Y.L., A.M.-B., A.M.-G., I.G. and N.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Jee-Young Lee.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks Y. Compta and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Lewy bodies

Eosinophilic intracytoplasmic neuronal inclusions, composed largely of α-synuclein, that are characteristically found in the brain of individuals with neurodegenerative diseases such as Parkinson disease and dementia with Lewy bodies.

Nigrosomes

Clusters of calbindin-negative dopaminergic cells in the substantia nigra.

Melanophagia

Phagocytosis of melanin.

Neuronophagia

Destruction of neurons by phagocytic cells.

Marinesco bodies

Intranuclear inclusions found in pigmented neurons in the substantia nigra.

Somatodendrite

Region of a neuron that includes the cell body and dendrite.

Single-shell scans

Diffusion signal scans acquired in a single shell.

Multi-shell scans

Diffusion signal scans acquired from a multi-shell scheme.

Free water fractional volume

The volume fraction of free water within the regional volume defined by a voxel.

Bi-tensor modelling

A diffusion tensor imaging analysis model consisting of two tensor compartments; for example, free water and tissue compartments.

Fractional anisotropy

A measure of the degree of anisotropy of water molecules in diffusion tensor imaging analysis, which ranges from 0 (infinite isotropy, no restrictions in all directions) to 1 (anisotropy, movement in only one axis and limited to others).

Hoehn and Yahr stages

Clinical staging system for parkinsonian disorders proposed by M. Hoehn and Y. Yahr in 1967.

Partial volume

The actual volume occupied by a small species of molecules or particles in a solution.

Region of interest (ROI) analysis

Analysis of data extracted from specified ROIs for the study.

Quantitative susceptibility mapping

(QSM). An MRI technique for quantifying the spatial distribution of magnetic susceptibility within the tissue.

T2* dephasing

Immediately after forming transverse magnetization by a radiofrequency pulse, the transverse magnetization starts decreasing in magnitude as protons start going out of phase (dephasing). Dephasing can be altered by magnetic field inhomogeneity, magnetic susceptibility difference of various elements in the tissues, and the gradients applied. T2* relaxation is the decay of transverse magnetization with gradient echo sequences, which is used to visualize haemorrhage, calcification and iron deposition.

Fast spin-echo

An MRI technique that records multiple echoes after a 90° excitation pulse by transmitting a series of 180° inversion pulses at set intervals. By contrast, the conventional spin-echo sequence measures a single echo.

Magnetization transfer

The transfer of nuclear spin polarization and/or coherence from one population of nuclei to another. This technique can suppress background signals to improve contrast on MRI scans.

Area under the curve

(AUC). Area under the receiver operating characteristic curve (integral) ranging from 0 (no discriminative ability) to 1 (the highest-level ability) to evaluate an ability of a classifier under a classification threshold.

Scotopic and photopic b-waves

Short flashes can elicit an electroretinogram consisting of initial negative deflection (a-wave) and a following positive deflection (b-wave). The b-waves in response to scotopic and photopic stimuli reflect rod and cone ON bipolar cell depolarization, respectively.

Optical interferometry

A measurement method using the phenomenon of interference of light waves. Medical imaging using low-coherence interferometry can provide tomographic visualization of internal tissue microstructure.

Peripapillary retinal nerve fibre layer

(pRNFL). Retinal nerve fibre layer bundle that passes through the optic papilla (optic disc).

Honeymoon phase

A period of relative stability with an excellent response to levodopa in patients with Parkinson disease, which usually lasts for a few years following the start of levodopa therapy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lee, JY., Martin-Bastida, A., Murueta-Goyena, A. et al. Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease. Nat Rev Neurol 18, 203–220 (2022). https://doi.org/10.1038/s41582-022-00618-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-022-00618-9

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing