Top

Published in:

Open Access 01-03-2019 | Intense Pulsed Light | Review

Retinal α-synuclein deposits in Parkinson’s disease patients and animal models

Authors: Lien Veys, Marjan Vandenabeele, Isabel Ortuño-Lizarán, Veerle Baekelandt, Nicolás Cuenca, Lieve Moons, Lies De Groef

Published in: Acta Neuropathologica | Issue 3/2019

Abstract

Despite decades of research, accurate diagnosis of Parkinson’s disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson’s disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson’s disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson’s disease patients. An expanding number of clinical studies have investigated the use of in vivo assessments of retinal structure, electrophysiological function, and vision-driven tasks as novel means for identifying patients at risk that need further neurological examination and for longitudinal follow-up of disease progression in Parkinson’s disease patients. Often, the results of these studies have been interpreted in relation to α-synuclein deposits and dopamine deficiency in the retina, mirroring the defining pathological features of Parkinson’s disease in the brain. To better understand the visual defects seen in Parkinson’s disease patients and to propel the use of retinal changes as biomarkers for Parkinson’s disease, however, more conclusive neuropathological evidence for the presence of retinal α-synuclein aggregates, and its relation to the cerebral α-synuclein burden, is urgently needed. This review provides a comprehensive and critical overview of the research conducted to unveil α-synuclein aggregates in the retina of Parkinson’s disease patients and animal models, and thereby aims to aid the ongoing discussion about the potential use of the retinal changes and/or visual symptoms as biomarkers for Parkinson’s disease.

Adam CR, Shrier E, Ding Y, Glazman S, Bodis-Wollner I (2013) Correlation of inner retinal thickness evaluated by spectral-domain optical coherence tomography and contrast sensitivity in Parkinson disease. J Neuroophthalmol 33:137–142. https://doi.org/10.1097/WNO.0b013e31828c4e1a PubMedCrossRef

Alafuzoff I, Parkkinen L, Al-Sarraj S, Arzberger T, Bell J, Bodi I et al (2008) Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 67:125–143. https://doi.org/10.1097/nen.0b013e3181633526 PubMedCrossRef

Alonso R, Gonzalez-Moron D, Garcea O (2018) Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: a review. Mult Scler Relat Disord 22:77–82. https://doi.org/10.1016/j.msard.2018.03.007 PubMedCrossRef

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

Alzheimer’sAssociation (2017) Alzheimer’s disease facts and figures. Alzheimer’s Dement 13:325–373CrossRef

Ang M, Tan ACS, Cheung CMG, Keane PA, Dolz-Marco R, Sng CCA et al (2018) Optical coherence tomography angiography: a review of current and future clinical applications. Graefes Arch Clin Exp Ophthalmol 256:237–245. https://doi.org/10.1007/s00417-017-3896-2 PubMedCrossRef

Archibald NK, Clarke MP, Mosimann UP, Burn DJ (2009) The retina in Parkinson’s disease. Brain 132:1128–1145. https://doi.org/10.1093/brain/awp068 PubMedCrossRef

Archibald NK, Clarke MP, Mosimann UP, Burn DJ (2011) Visual symptoms in Parkinson’s disease and Parkinson’s disease dementia. Mov Disord 26:2387–2395. https://doi.org/10.1002/mds.23891 PubMedCrossRef

Armstrong RA (2011) Visual signs and symptoms of progressive supranuclear palsy. Clin Exp Optom 94:150–160. https://doi.org/10.1111/j.1444-0938.2010.00504.x PubMedCrossRef

10.

Armstrong RA (2011) Visual symptoms in Parkinson’s disease. Parkinsons Dis 2011:908306. https://doi.org/10.4061/2011/908306 PubMedPubMedCentralCrossRef

11.

Armstrong RA (2015) Oculo-visual dysfunction in parkinson’s disease. J Parkinsons Dis 5:715–726. https://doi.org/10.3233/JPD-150686 PubMedPubMedCentralCrossRef

12.

Aydin TS, Umit D, Nur OM, Fatih U, Asena K, Nefise OY et al (2018) Optical coherence tomography findings in Parkinson’s disease. Kaohsiung J Med Sci 34:166–171. https://doi.org/10.1016/j.kjms.2017.11.006 PubMedCrossRef

13.

Bajwa A, Aman R, Reddy AK (2015) A comprehensive review of diagnostic imaging technologies to evaluate the retina and the optic disk. Int Ophthalmol 35:733–755. https://doi.org/10.1007/s10792-015-0087-1 PubMedCrossRef

14.

Balendra SI, Normando EM, Bloom PA, Cordeiro MF (2015) Advances in retinal ganglion cell imaging. Eye (London, England) 29:1260–1269. https://doi.org/10.1038/eye.2015.154 CrossRef

15.

Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI et al (2014) Phosphorylated alpha-synuclein-immunoreactive retinal neuronal elements in Parkinson’s disease subjects. Neurosci Lett 571:34–38. https://doi.org/10.1016/j.neulet.2014.04.027 PubMedPubMedCentralCrossRef

16.

Bertrand JA, Bedetti C, Postuma RB, Monchi O, Genier Marchand D, Jubault T et al (2012) Color discrimination deficits in Parkinson’s disease are related to cognitive impairment and white-matter alterations. Mov Disord 27:1781–1788. https://doi.org/10.1002/mds.25272 PubMedCrossRef

17.

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306. https://doi.org/10.1038/81834 PubMedCrossRef

18.

Bezard E, Yue Z, Kirik D, Spillantini MG (2013) Animal models of Parkinson’s disease: limits and relevance to neuroprotection studies. Mov Disord 28:61–70. https://doi.org/10.1002/mds.25108 PubMedCrossRef

19.

Bodis-Wollner I (2013) Foveal vision is impaired in Parkinson’s disease. Parkinsonism Relat Disord 19:1–14. https://doi.org/10.1016/j.parkreldis.2012.07.012 PubMedCrossRef

20.

Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S (2014) alpha-synuclein in the inner retina in parkinson disease. Ann Neurol 75:964–966. https://doi.org/10.1002/ana.24182 PubMedCrossRef

21.

Bodis-Wollner I, Marx MS, Mitra S, Bobak P, Mylin L, Yahr M (1987) Visual dysfunction in Parkinson’s disease. Loss in spatiotemporal contrast sensitivity. Brain 110(Pt 6):1675–1698PubMedCrossRef

22.

Bodis-Wollner I, Miri S, Glazman S (2014) Venturing into the no-man’s land of the retina in Parkinson’s disease. Mov Disord 29:15–22. https://doi.org/10.1002/mds.25741 PubMedCrossRef

23.

Bodis-Wollner I, Tzelepi A (1998) 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. Vision Res 38:1479–1487PubMedCrossRef

24.

Boeke A, Rosen D, Mastrianni J, Xie T, Bernard J (2016) Optical coherence tomography as potential biomarker in parkinson’s disease and Alzheimer’s disease (P5.177). Neurology 86:P5–P177

25.

Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134. https://doi.org/10.1007/s00441-004-0956-9 PubMedCrossRef

26.

Brundin P, Melki R (2017) Prying into the prion hypothesis for Parkinson’s disease. J Neurosci 37:9808–9818. https://doi.org/10.1523/JNEUROSCI.1788-16.2017 PubMedPubMedCentralCrossRef

27.

Burguera JA, Vilela C, Traba A, Ameave Y, Vallet M (1990) The electroretinogram and visual evoked potentials in patients with Parkinson’s disease. Arch Neurobiol (Madr) 53:1–7

28.

Cai W, Feng D, Schwarzschild MA, McLean PJ, Chen X (2018) Bimolecular fluorescence complementation of alpha-synuclein demonstrates its oligomerization with dopaminergic phenotype in mice. EBioMedicine 29:13–22. https://doi.org/10.1016/j.ebiom.2018.01.035 PubMedPubMedCentralCrossRef

29.

Cheung CY, Ikram MK, Chen C, Wong TY (2017) Imaging retina to study dementia and stroke. Prog Retin Eye Res 57:89–107. https://doi.org/10.1016/j.preteyeres.2017.01.001 PubMedCrossRef

30.

Chorostecki J, Seraji-Bozorgzad N, Shah A, Bao F, Bao G, George E et al (2015) Characterization of retinal architecture in Parkinson’s disease. J Neurol Sci 355:44–48. https://doi.org/10.1016/j.jns.2015.05.007 PubMedCrossRef

31.

Croisier E, Elfant D, Deprez M, Goldring K, Dexter DT, Pearce RK et al (2006) Comparative study of commercially available anti-alpha-synuclein antibodies. Neuropathol Appl Neurobiol 32:351–356. https://doi.org/10.1111/j.1365-2990.2006.00722.x PubMedCrossRef

32.

Cuenca N, Herrero MT, Angulo A, de Juan E, Martinez-Navarrete GC, Lopez S et al (2005) Morphological impairments in retinal neurons of the scotopic visual pathway in a monkey model of Parkinson’s disease. J Comp Neurol 493:261–273. https://doi.org/10.1002/cne.20761 PubMedCrossRef

33.

Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909PubMedCrossRef

34.

De Groef L, Cordeiro MF (2018) Is the eye an extension of the brain in central nervous system disease? J Ocul Pharmacol Ther 34:129–133. https://doi.org/10.1089/jop.2016.0180 PubMedCrossRef

35.

Deeg AA, Reiner AM, Schmidt F, Schueder F, Ryazanov S, Ruf VC et al (2015) Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to alpha-synuclein aggregates. Biochim Biophys Acta 1850:1884–1890. https://doi.org/10.1016/j.bbagen.2015.05.021 PubMedCrossRef

36.

Dehay B, Bourdenx M, Gorry P, Przedborski S, Vila M, Hunot S et al (2015) Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol 14:855–866. https://doi.org/10.1016/s1474-4422(15)00006-x PubMedPubMedCentralCrossRef

37.

Dhillon JS, Riffe C, Moore BD, Ran Y, Chakrabarty P, Golde TE et al (2017) A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. PLoS One 12:e0184731. https://doi.org/10.1371/journal.pone.0184731 PubMedPubMedCentralCrossRef

38.

Diederich NJ, Raman R, Leurgans S, Goetz CG (2002) Progressive worsening of spatial and chromatic processing deficits in Parkinson disease. Arch Neurol 59:1249–1252PubMedCrossRef

39.

Djamgoz MB, Hankins MW, Hirano J, Archer SN (1997) Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Res 37:3509–3529. https://doi.org/10.1016/s0042-6989(97)00129-6 PubMedCrossRef

40.

Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164:1357–1391. https://doi.org/10.1111/j.1476-5381.2011.01426.x PubMedPubMedCentralCrossRef

41.

Eschbach J, Danzer KM (2014) alpha-Synuclein in Parkinson’s disease: pathogenic function and translation into animal models. Neurodegener Dis 14:1–17. https://doi.org/10.1159/000354615 PubMedCrossRef

42.

Esteve-Rudd J, Fernandez-Sanchez L, Lax P, De Juan E, Martin-Nieto J, Cuenca N (2011) Rotenone induces degeneration of photoreceptors and impairs the dopaminergic system in the rat retina. Neurobiol Dis 44:102–115. https://doi.org/10.1016/j.nbd.2011.06.009 PubMedCrossRef

43.

Frost, Sullivan (2017) Therapeutic breakthroughs in Alzheimer’s and Parkinson’s disease. http://www.frost.com/sublib/display-report.do?id=D7B4-01-00-00-00

44.

Galvao J, Davis BM, Cordeiro MF (2013) In vivo imaging of retinal ganglion cell apoptosis. Curr Opin Pharmacol 13:123–127. https://doi.org/10.1016/j.coph.2012.08.007 PubMedCrossRef

45.

Garcia-Martin E, Rodriguez-Mena D, Satue M, Almarcegui C, Dolz I, Alarcia R et al (2014) Electrophysiology and optical coherence tomography to evaluate Parkinson disease severity. Invest Ophthalmol Vis Sci 55:696–705. https://doi.org/10.1167/iovs.13-13062 PubMedCrossRef

46.

Ghilardi MF, Bodis-Wollner I, Onofrj MC, Marx MS, Glover AA (1988) Spatial frequency-dependent abnormalities of the pattern electroretinogram and visual evoked potentials in a parkinsonian monkey model. Brain 111(Pt 1):131–149PubMedCrossRef

47.

Giraldez-Perez R, Antolin-Vallespin M, Munoz M, Sanchez-Capelo A (2014) Models of alpha-synuclein aggregation in Parkinson’s disease. Acta Neuropathol Commun 2:176. https://doi.org/10.1186/s40478-014-0176-9 PubMedPubMedCentralCrossRef

48.

Gottlob I, Schneider E, Heider W, Skrandies W (1987) Alteration of visual evoked potentials and electroretinograms in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 66:349–357PubMedCrossRef

49.

Guo L, Normando EM, Shah PA, De Groef L, Cordeiro MF (2018) Oculo-visual abnormalities in Parkinson’s disease: possible value as biomarkers. Mov Disord 33:1390–1406. https://doi.org/10.1002/mds.27454 PubMedCrossRef

50.

Halliday G, Herrero MT, Murphy K, McCann H, Ros-Bernal F, Barcia C et al (2009) No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism. Mov Disord 24:1519–1523. https://doi.org/10.1002/mds.22481 PubMedCrossRef

51.

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

52.

Haug BA, Trenkwalder C, Arden GB, Oertel WH, Paulus W (1994) Visual thresholds to low-contrast pattern displacement, color contrast, and luminance contrast stimuli in Parkinson’s disease. Mov Disord 9:563–570. https://doi.org/10.1002/mds.870090510 PubMedCrossRef

53.

Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG (2014) Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer’s and Parkinson’s disease patients. Brain Pathol 24:25–32. https://doi.org/10.1111/bpa.12070 PubMedCrossRef

54.

Holroyd S, Currie L, Wooten GF (2001) Prospective study of hallucinations and delusions in Parkinson’s disease. J Neurol Neurosurg Psychiatry 70:734–738PubMedPubMedCentralCrossRef

55.

Huang L, Deng M, He Y, Lu S, Liu S, Fang Y (2016) beta-asarone increases MEF2D and TH levels and reduces alpha-synuclein level in 6-OHDA-induced rats via regulating the HSP70/MAPK/MEF2D/Beclin-1 pathway: chaperone-mediated autophagy activation, macroautophagy inhibition and HSP70 up-expression. Behav Brain Res 313:370–379. https://doi.org/10.1016/j.bbr.2016.07.028 PubMedCrossRef

56.

Huang YM, Yin ZQ (2011) Minor retinal degeneration in Parkinson’s disease. Med Hypotheses 76:194–196. https://doi.org/10.1016/j.mehy.2010.09.016 PubMedCrossRef

57.

Ikeda H, Head GM, Ellis CJ (1994) Electrophysiological signs of retinal dopamine deficiency in recently diagnosed Parkinson’s disease and a follow up study. Vision Res 34:2629–2638PubMedCrossRef

58.

Inzelberg R, Ramirez JA, Nisipeanu P, Ophir A (2004) Retinal nerve fiber layer thinning in Parkinson disease. Vision Res 44:2793–2797. https://doi.org/10.1016/j.visres.2004.06.009 PubMedCrossRef

59.

Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S (2015) Evaluation of models of Parkinson’s disease. Front Neurosci 9:503. https://doi.org/10.3389/fnins.2015.00503 PubMedCrossRef

60.

Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376. https://doi.org/10.1136/jnnp.2007.131045 PubMedCrossRef

61.

Jones RD, Donaldson IM, Timmings PL (1992) Impairment of high-contrast visual acuity in Parkinson’s disease. Mov Disord 7:232–238. https://doi.org/10.1002/mds.870070308 PubMedCrossRef

62.

Kayabasi U, Sergott RC, Rispoli M (2014) Retinal examination for the diagnosis of Alzheimers disease. Int J Ophthalmol Clin Res. https://doi.org/10.23937/2378-346X/1410002 CrossRef

63.

Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL et al (2011) Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage 54(Suppl 1):S204–S217. https://doi.org/10.1016/j.neuroimage.2010.06.020 PubMedCrossRef

64.

Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ et al (2017) Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight. https://doi.org/10.1172/jci.insight.93621 PubMedPubMedCentralCrossRef

65.

Koronyo Y, Salumbides BC, Black KL, Koronyo-Hamaoui M (2012) Alzheimer’s disease in the retina: imaging retinal abeta plaques for early diagnosis and therapy assessment. Neurodegener Dis 10:285–293. https://doi.org/10.1159/000335154 PubMedCrossRef

66.

Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N et al (2012) An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology. Acta Neuropathol (Berl) 124:37–50. https://doi.org/10.1007/s00401-012-0964-x CrossRef

67.

Kumar S, Ho G, Zhang Y, Zhuo L (2010) In vivo imaging of retinal gliosis: a platform for diagnosis of PD and Screening of anti-PD compounds. Conf Proc 2010:3049–3052. https://doi.org/10.1109/iembs.2010.5626122 CrossRef

68.

La Morgia C, Barboni P, Rizzo G, Carbonelli M, Savini G, Scaglione C et al (2013) Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern? Eur J Neurol 20:198–201. https://doi.org/10.1111/j.1468-1331.2012.03701.x PubMedCrossRef

69.

Langheinrich T, Tebartz van Elst L, Lagreze WA, Bach M, Lucking CH, Greenlee MW (2000) Visual contrast response functions in Parkinson’s disease: evidence from electroretinograms, visually evoked potentials and psychophysics. Clin Neurophysiol 111:66–74PubMedCrossRef

70.

Lee JY, Ahn J, Kim TW, Jeon BS (2014) Optical coherence tomography in Parkinson’s disease: is the retina a biomarker? J Parkinsons Dis 4:197–204PubMed

71.

Lee JY, Kim JM, Ahn J, Kim HJ, Jeon BS, Kim TW (2014) Retinal nerve fiber layer thickness and visual hallucinations in Parkinson’s Disease. Mov Disord 29:61–67. https://doi.org/10.1002/mds.25543 PubMedCrossRef

72.

Leger F, Fernagut PO, Canron MH, Leoni S, Vital C, Tison F et al (2011) Protein aggregation in the aging retina. J Neuropathol Exp Neurol 70:63–68. https://doi.org/10.1097/NEN.0b013e31820376cc PubMedCrossRef

73.

Levin J, Schmidt F, Boehm C, Prix C, Bötzel K, Ryazanov S et al (2014) The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol 127:779–780. https://doi.org/10.1007/s00401-014-1265-3 PubMedPubMedCentralCrossRef

74.

Liberski PP, Yanagihara R, Gibbs CJ Jr, Gajdusek DC (1990) Spread of Creutzfeldt-Jakob disease virus along visual pathways after intraocular inoculation. Arch Virol 111:141–147PubMedCrossRef

75.

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

76.

Ma MR, Hu ZW, Zhao YF, Chen YX, Li YM (2016) Phosphorylation induces distinct alpha-synuclein strain formation. Sci Rep 6:37130. https://doi.org/10.1038/srep37130 PubMedPubMedCentralCrossRef

77.

Mahlknecht P, Seppi K, Poewe W (2015) The concept of prodromal Parkinson’s disease. J Parkinsons Dis 5:681–697. https://doi.org/10.3233/JPD-150685 PubMedPubMedCentralCrossRef

78.

Mammadova N, Summers CM, Kokemuller RD, He Q, Ding S, Baron T et al (2018) Accelerated accumulation of retinal alpha-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson’s disease. Neurobiol Dis 121:1–16. https://doi.org/10.1016/j.nbd.2018.09.013 PubMedCrossRef

79.

Maresca A, la Morgia C, Caporali L, Valentino ML, Carelli V (2013) The optic nerve: a “mito-window” on mitochondrial neurodegeneration. Mol Cell Neurosci 55:62–76. https://doi.org/10.1016/j.mcn.2012.08.004 PubMedPubMedCentralCrossRef

80.

Marsili L, Rizzo G, Colosimo C (2018) Diagnostic criteria for parkinson’s disease: from James Parkinson to the concept of prodromal disease. Front Neurol 9:156. https://doi.org/10.3389/fneur.2018.00156 PubMedPubMedCentralCrossRef

81.

Martinez-Martin P, Rodriguez-Blazquez C, Mario A, Arakaki T, Arillo VC, Chana P et al (2015) Parkinson’s disease severity levels and MDS-Unified Parkinson’s Disease Rating Scale. Parkinsonism Relat Disord 21:50–54. https://doi.org/10.1016/j.parkreldis.2014.10.026 PubMedCrossRef

82.

Martinez-Navarrete GC, Martin-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N (2007) Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis 13:949–961PubMedPubMedCentral

83.

Mathur S, DeWitte S, Robledo I, Isaacs T, Stamford J (2015) Rising to the challenges of clinical trial improvement in Parkinson’s disease. J Parkinsons Dis 5:263–268. https://doi.org/10.3233/jpd-150541 PubMedCrossRef

84.

Matlach J, Wagner M, Malzahn U, Schmidtmann I, Steigerwald F, Musacchio T et al (2018) Retinal changes in Parkinson’s disease and glaucoma. Parkinsonism Relat Disord. https://doi.org/10.1016/j.parkreldis.2018.06.016 PubMedCrossRef

85.

Matsui H, Udaka F, Tamura A, Oda M, Kubori T, Nishinaka K et al (2006) Impaired visual acuity as a risk factor for visual hallucinations in Parkinson’s disease. J Geriatr Psychiatry Neurol 19:36–40. https://doi.org/10.1177/0891988705284739 PubMedCrossRef

86.

Mazzarella J, Cole J (2016) All eyes on neurodegenerative diseases. Rev Optometry. https://www.reviewofoptometry.com/article/all-eyes-on-neurodegenerative-disease

87.

Meng T, Zheng ZH, Liu TT, Lin L (2012) Contralateral retinal dopamine decrease and melatonin increase in progression of hemiparkinsonium rat. Neurochem Res 37:1050–1056. https://doi.org/10.1007/s11064-012-0706-4 PubMedCrossRef

88.

Miri S, Shrier EM, Glazman S, Ding Y, Selesnick I, Kozlowski PB et al (2015) The avascular zone and neuronal remodeling of the fovea in Parkinson disease. Ann Clin Transl Neurol 2:196–201. https://doi.org/10.1002/acn3.146 PubMedPubMedCentralCrossRef

89.

More SS, Beach JM, Vince R (2016) Early detection of amyloidopathy in Alzheimer’s mice by hyperspectral endoscopy. Invest Ophthalmol Vis Sci 57:3231–3238. https://doi.org/10.1167/iovs.15-17406 PubMedCrossRef

90.

More SS, Vince R (2015) Hyperspectral imaging signatures detect amyloidopathy in Alzheimer’s mouse retina well before onset of cognitive decline. ACS Chem Neurosci 6:306–315. https://doi.org/10.1021/cn500242z PubMedCrossRef

91.

Moschos MM, Tagaris G, Markopoulos I, Margetis I, Tsapakis S, Kanakis M et al (2011) Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. Eur J Ophthalmol 21:24–29PubMedCrossRef

92.

Nightingale S, Mitchell KW, Howe JW (1986) Visual evoked cortical potentials and pattern electroretinograms in Parkinson’s disease and control subjects. J Neurol Neurosurg Psychiatry 49:1280–1287PubMedPubMedCentralCrossRef

93.

Normando EM, Davis BM, De Groef L, Nizari S, Turner LA, Ravindran N et al (2016) The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson’s disease: evidence for a neuroprotective effect of rosiglitazone in the eye and brain. Acta Neuropathol Commun 4:86. https://doi.org/10.1186/s40478-016-0346-z PubMedPubMedCentralCrossRef

94.

Nowacka B, Lubinski W, Honczarenko K, Potemkowski A, Safranow K (2014) Ophthalmological features of Parkinson disease. Med Sci Monit 20:2243–2249. https://doi.org/10.12659/MSM.890861 PubMedPubMedCentralCrossRef

95.

Nowacka B, Lubiński W, Honczarenko K, Potemkowski A, Safranow K (2015) Bioelectrical function and structural assessment of the retina in patients with early stages of Parkinson’s disease (PD). Doc Ophthalmol 131:95–104. https://doi.org/10.1007/s10633-015-9503-0 PubMedPubMedCentralCrossRef

96.

Oliveras-Salva M, Van der Perren A, Casadei N, Stroobants S, Nuber S, D’Hooge R et al (2013) rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol Neurodegener 8:44. https://doi.org/10.1186/1750-1326-8-44 PubMedPubMedCentralCrossRef

97.

Ong SS, Doraiswamy PM, Lad EM (2018) Controversies and Future directions of ocular biomarkers in Alzheimer disease. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2018.0602 PubMedCentralCrossRefPubMed

98.

Ortuno-Lizaran I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N (2018) Phosphorylated alpha-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. https://doi.org/10.1002/mds.27392 PubMedCrossRefPubMedCentral

99.

Ortuno-Lizaran I, Esquiva G, Beach TG, Serrano GE, Adler CH, Lax P et al (2018) Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson’s disease. Acta Neuropathol Commun 6:90. https://doi.org/10.1186/s40478-018-0596-z PubMedPubMedCentralCrossRef

100.

Oueslati A (2016) Implication of alpha-synuclein phosphorylation at S129 in synucleinopathies: what have we learned in the last decade? J Parkinsons Dis 6:39–51. https://doi.org/10.3233/jpd-160779 PubMedPubMedCentralCrossRef

101.

Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ et al (2015) Intrastriatal injection of pre-formed mouse alpha-synuclein fibrils into rats triggers alpha-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185–199. https://doi.org/10.1016/j.nbd.2015.06.003 PubMedPubMedCentralCrossRef

102.

Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. https://doi.org/10.1038/nature14547 PubMedCrossRef

103.

Peppe A, Stanzione P, Pierantozzi M, Semprini R, Bassi A, Santilli AM et al (1998) Does pattern electroretinogram spatial tuning alteration in Parkinson’s disease depend on motor disturbances or retinal dopaminergic loss? Electroencephalogr Clin Neurophysiol 106:374–382PubMedCrossRef

104.

Peppe A, Stanzione P, Pierelli F, De Angelis D, Pierantozzi M, Bernardi G (1995) Visual alterations in de novo Parkinson’s disease: pattern electroretinogram latencies are more delayed and more reversible by levodopa than are visual evoked potentials. Neurology 45:1144–1148PubMedCrossRef

105.

Peppe A, Stanzione P, Pierelli F, Stefano E, Rizzo PA, Tagliati M et al (1992) Low contrast stimuli enhance PERG sensitivity to the visual dysfunction in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 82:453–457PubMedCrossRef

106.

Pikkarainen M, Martikainen P, Alafuzoff I (2010) The effect of prolonged fixation time on immunohistochemical staining of common neurodegenerative disease markers. J Neuropathol Exp Neurol 69:40–52. https://doi.org/10.1097/NEN.0b013e3181c6c13d PubMedCrossRef

107.

Poewe W (2008) Non-motor symptoms in Parkinson’s disease. Eur J Neurol 15(Suppl 1):14–20. https://doi.org/10.1111/j.1468-1331.2008.02056.x PubMedCrossRef

108.

Polinski NK, Volpicelli-Daley LA, Sortwell CE, Luk KC, Cremades N, Gottler LM et al (2018) Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson’s disease in rodents. J Parkinsons Dis. https://doi.org/10.3233/jpd-171248 PubMedPubMedCentralCrossRef

109.

Polo V, Satue M, Rodrigo MJ, Otin S, Alarcia R, Bambo MP et al (2016) Visual dysfunction and its correlation with retinal changes in patients with Parkinson’s disease: an observational cross-sectional study. BMJ Open 6:e009658. https://doi.org/10.1136/bmjopen-2015-009658 PubMedPubMedCentralCrossRef

110.

Possin KL (2010) Visual spatial cognition in neurodegenerative disease. Neurocase 16:466–487. https://doi.org/10.1080/13554791003730600 PubMedPubMedCentralCrossRef

111.

Postuma RB, Berg D (2017) The new diagnostic criteria for parkinson’s disease. Int Rev Neurobiol 132:55–78. https://doi.org/10.1016/bs.irn.2017.01.008 PubMedCrossRef

112.

Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W et al (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30:1591–1601. https://doi.org/10.1002/mds.26424 PubMedCrossRef

113.

Price DL, Rockenstein E, Mante M, Adame A, Overk C, Spencer B et al (2016) Longitudinal live imaging of retinal alpha-synuclein:GFP deposits in a transgenic mouse model of Parkinson’s Disease/Dementia with Lewy Bodies. Sci Rep 6:29523. https://doi.org/10.1038/srep29523 PubMedPubMedCentralCrossRef

114.

Price MJ, Feldman RG, Adelberg D, Kayne H (1992) Abnormalities in color vision and contrast sensitivity in Parkinson’s disease. Neurology 42:887–890PubMedCrossRef

115.

Rahimi J, Milenkovic I, Kovacs GG (2015) Patterns of Tau and alpha-Synuclein pathology in the visual system. J Parkinsons Dis 5:333–340. https://doi.org/10.3233/JPD-140485 PubMedCrossRef

116.

Recasens A, Dehay B (2014) Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 8:159. https://doi.org/10.3389/fnana.2014.00159 PubMedPubMedCentralCrossRef

117.

Reiner AM, Schmidt F, Ryazanov S, Leonov A, Weckbecker D, Deeg AA et al (2017) Photophysics of diphenyl-pyrazole compounds in solutions and α-synuclein aggregates. BBA Gen Subj 22:22. https://doi.org/10.1016/j.bbagen.2017.12.007 CrossRef

118.

Richter F (2018) Lighting up alpha-synuclein oligomers. EBioMedicine 29:3–4. https://doi.org/10.1016/j.ebiom.2018.02.016 PubMedPubMedCentralCrossRef

119.

Rojas JC, Saavedra JA, Gonzalez-Lima F (2008) Neuroprotective effects of memantine in a mouse model of retinal degeneration induced by rotenone. Brain Res 1215:208–217. https://doi.org/10.1016/j.brainres.2008.04.001 PubMedPubMedCentralCrossRef

120.

Santano C, Perez de Lara M, Pintor J (2011) Retinal disturbances in patients and animal models with Huntington’s, Parkinson’s and Alzheimer’s disease. In: Basu S, Wiklund L (eds) Oxidative stress in applied basic research and clinical practice—studies on experimental models. Humana, New York, pp 221–250

121.

Sartucci F, Orlandi G, Bonuccelli U, Borghetti D, Murri L, Orsini C et al (2006) Chromatic pattern-reversal electroretinograms (ChPERGs) are spared in multiple system atrophy compared with Parkinson’s disease. Neurol Sci 26:395–401. https://doi.org/10.1007/s10072-006-0522-1 PubMedPubMedCentralCrossRef

122.

Sartucci F, Porciatti V (2006) 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. https://doi.org/10.1097/01.wnp.0000216127.53517.4d PubMedPubMedCentralCrossRef

123.

Sasaguri H, Nilsson P, Hashimoto S, Nagata K, Saito T, De Strooper B et al (2017) APP mouse models for Alzheimer’s disease preclinical studies. EMBO J 36:2473–2487. https://doi.org/10.15252/embj.201797397 PubMedPubMedCentralCrossRef

124.

Satue M, Rodrigo MJ, Otin S, Bambo MP, Fuertes MI, Ara JR et al (2016) Relationship between visual dysfunction and retinal changes in patients with multiple sclerosis. PLoS One 11:e0157293. https://doi.org/10.1371/journal.pone.0157293 PubMedPubMedCentralCrossRef

125.

Schneider JS, Ault ME, Anderson DW (2014) Retinal pathology detected by optical coherence tomography in an animal model of Parkinson’s disease. Mov Disord 29:1547–1551. https://doi.org/10.1002/mds.25974 PubMedCrossRef

126.

Shah TM, Gupta SM, Chatterjee P, Campbell M, Martins RN (2017) Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer’s disease. Mol Psychiatry 22:353–363. https://doi.org/10.1038/mp.2016.251 PubMedCrossRef

127.

Sherer TB, Kim JH, Betarbet R, Greenamyre JT (2003) Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp Neurol 179:9–16PubMedCrossRef

128.

Shrier EM, Adam CR, Spund B, Glazman S, Bodis-Wollner I (2012) Interocular asymmetry of foveal thickness in Parkinson disease. J Ophthalmol 2012:728457. https://doi.org/10.1155/2012/728457 PubMedPubMedCentralCrossRef

129.

Shults CW (2006) Lewy bodies. Proc Natl Acad Sci USA 103:1661–1668. https://doi.org/10.1073/pnas.0509567103 PubMedCrossRef

130.

Silva MF, Faria P, Regateiro FS, Forjaz V, Januario C, Freire A et al (2005) Independent patterns of damage within magno-, parvo- and koniocellular pathways in Parkinson’s disease. Brain 128:2260–2271. https://doi.org/10.1093/brain/awh581 PubMedCrossRef

131.

Singh PK, Kotia V, Ghosh D, Mohite GM, Kumar A, Maji SK (2013) Curcumin modulates alpha-synuclein aggregation and toxicity. ACS Chem Neurosci 4:393–407. https://doi.org/10.1021/cn3001203 PubMedCrossRef

132.

Snyder PJ, Johnson LN, Lim YY, Santos CY, Alber J, Maruff P et al (2016) Nonvascular retinal imaging markers of preclinical Alzheimer’s disease. Alzheimers Dement (Amst) 4:169–178. https://doi.org/10.1016/j.dadm.2016.09.001 CrossRef

133.

Spund B, Ding Y, Liu T, Selesnick I, Glazman S, Shrier EM et al (2013) Remodeling of the fovea in Parkinson disease. J Neural Transm (Vienna) 120:745–753. https://doi.org/10.1007/s00702-012-0909-5 CrossRef

134.

Stenc Bradvica I, Mihaljevic I, Butkovic-Soldo S, Kadojic D, Titlic M, Bradvica M et al (2015) Transcranial sonography and the pocket smell test in the differential diagnosis between parkinson’s disease and essential tremor. Neurol Sci 36:1403–1410. https://doi.org/10.1007/s10072-015-2152-y PubMedCrossRef

135.

Tagliati M, Bodis-Wollner I, Kovanecz I, Stanzione P (1994) Spatial frequency tuning of the monkey pattern ERG depends on D2 receptor-linked action of dopamine. Vis Res 34:2051–2057PubMedCrossRef

136.

Tatton WG, Kwan MM, Verrier MC, Seniuk NA, Theriault E (1990) MPTP produces reversible disappearance of tyrosine hydroxylase-containing retinal amacrine cells. Brain Res 527:21–31PubMedCrossRef

137.

Thakur P, Breger LS, Lundblad M, Wan OW, Mattsson B, Luk KC et al (2017) Modeling Parkinson’s disease pathology by combination of fibril seeds and alpha-synuclein overexpression in the rat brain. Proc Natl Acad Sci US A 114:E8284–E8293. https://doi.org/10.1073/pnas.1710442114 CrossRef

138.

Turcano P, Chen JJ, Bureau BL, Savica R (2018) Early ophthalmologic features of Parkinson’s disease: a review of preceding clinical and diagnostic markers. J Neurol. https://doi.org/10.1007/s00415-018-9051-0 PubMedCrossRef

139.

Ucak T, Alagoz A, Cakir B, Celik E, Bozkurt E, Alagoz G (2016) 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. https://doi.org/10.1016/j.parkreldis.2016.07.004 PubMedCrossRef

140.

Van der Perren A, Toelen J, Casteels C, Macchi F, Van Rompuy AS, Sarre S et al (2015) Longitudinal follow-up and characterization of a robust rat model for Parkinson’s disease based on overexpression of alpha-synuclein with adeno-associated viral vectors. Neurobiol Aging 36:1543–1558. https://doi.org/10.1016/j.neurobiolaging.2014.11.015 PubMedCrossRef

141.

Vingill S, Connor-Robson N, Wade-Martins R (2017) Are rodent models of Parkinson’s disease behaving as they should? Behav Brain Res. https://doi.org/10.1016/j.bbr.2017.10.021 PubMedCrossRef

142.

Volpicelli-Daley LA, Kirik D, Stoyka LE, Standaert DG, Harms AS (2016) How can rAAV-alpha-synuclein and the fibril alpha-synuclein models advance our understanding of Parkinson’s disease? J Neurochem 139(Suppl 1):131–155. https://doi.org/10.1111/jnc.13627 PubMedPubMedCentralCrossRef

143.

Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71. https://doi.org/10.1016/j.neuron.2011.08.033 PubMedPubMedCentralCrossRef

144.

Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J, Miklitz C et al (2015) Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol (Berl) 130:619–631. https://doi.org/10.1007/s00401-015-1483-3 CrossRef

145.

Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F et al (2013) Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol 125:795–813. https://doi.org/10.1007/s00401-013-1114-9 PubMedPubMedCentralCrossRef

146.

Watson R, Blamire AM, Colloby SJ, Wood JS, Barber R, He J et al (2012) Characterizing dementia with Lewy bodies by means of diffusion tensor imaging. Neurology 79:906–914. https://doi.org/10.1212/WNL.0b013e318266fc51 PubMedPubMedCentralCrossRef

147.

Webb RH, Hughes GW, Delori FC (1987) Confocal scanning laser ophthalmoscope. Appl Opt 26:1492–1499. https://doi.org/10.1364/ao.26.001492 PubMedCrossRef

148.

Weil RS, Schrag AE, Warren JD, Crutch SJ, Lees AJ, Morris HR (2016) Visual dysfunction in Parkinson’s disease. Brain 139:2827–2843. https://doi.org/10.1093/brain/aww175 PubMedPubMedCentralCrossRef

149.

Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC et al (2013) The Alzheimer’s Disease Neuroimaging Initiative: a review of papers published since its inception. Alzheimers Dement 9:e111–e194. https://doi.org/10.1016/j.jalz.2013.05.1769 PubMedPubMedCentralCrossRef

150.

Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 26(Suppl 1):S1–58. https://doi.org/10.1007/s10654-011-9581-6 PubMedCrossRef

151.

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

152.

Wong C, Ishibashi T, Tucker G, Hamasaki D (1985) Responses of the pigmented rabbit retina to NMPTP, a chemical inducer of parkinsonism. Exp Eye Res 40:509–519PubMedCrossRef

153.

Xu Y, Deng Y, Qing H (2015) The phosphorylation of alpha-synuclein: development and implication for the mechanism and therapy of the Parkinson’s disease. J Neurochem 135:4–18. https://doi.org/10.1111/jnc.13234 PubMedCrossRef

154.

Yin WL, Yin WG, Huang BS, Wu LX (2017) Neuroprotective effects of lentivirus-mediated cystathionine-beta-synthase overexpression against 6-OHDA-induced parkinson’s disease rats. Neurosci Lett 657:45–52. https://doi.org/10.1016/j.neulet.2017.07.019 PubMedCrossRef

155.

Zhang L, Liu L, Philip AL, Martinez JC, Guttierez JC, Marella M et al (2015) Long-term evaluation of Leber’s hereditary optic neuropathy-like symptoms in rotenone administered rats. Neurosci Lett 585:171–176. https://doi.org/10.1016/j.neulet.2014.12.004 PubMedCrossRef

156.

Zhang QS, Wang ZH, Zhang JL, Duan YL, Li GF, Zheng DL (2016) Beta-asarone protects against MPTP-induced Parkinson’s disease via regulating long non-coding RNA MALAT1 and inhibiting alpha-synuclein protein expression. Biomed Pharmacother 83:153–159. https://doi.org/10.1016/j.biopha.2016.06.017 PubMedCrossRef

157.

Zhang X, Jones D, Gonzalez-Lima F (2006) Neurodegeneration produced by rotenone in the mouse retina: a potential model to investigate environmental pesticide contributions to neurodegenerative diseases. J Toxicol Environ Health A 69:1681–1697. https://doi.org/10.1080/15287390600630203 PubMedCrossRef

158.

Zhang Y, Long H, Zhou F, Zhu W, Ruan J, Zhao Y et al (2017) Echinacoside’s nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin. J Cell Mol Med 21:3761–3775. https://doi.org/10.1111/jcmm.13285 PubMedPubMedCentralCrossRef

Title: Retinal α-synuclein deposits in Parkinson’s disease patients and animal models
Authors: Lien Veys
Marjan Vandenabeele
Isabel Ortuño-Lizarán
Veerle Baekelandt
Nicolás Cuenca
Lieve Moons
Lies De Groef
Publication date: 01-03-2019
Publisher: Springer Berlin Heidelberg
Keywords: Intense Pulsed Light
Parkinson's Disease
Biomarkers
Published in: Acta Neuropathologica / Issue 3/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-01956-z

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Retinal α-synuclein deposits in Parkinson’s disease patients and animal models

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2019

Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies

Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo

Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study

ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)