Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer’s disease

Autoři: Angela J. Oh aff001;  Giulia Amore aff001;  William Sultan aff001;  Samuel Asanad aff001;  Jason C. Park aff003;  Martina Romagnoli aff002;  Chiara La Morgia aff002;  Rustum Karanjia aff001;  Michael G. Harrington aff006;  Alfredo A. Sadun aff001
Působiště autorů: Doheny Eye institute, UCLA Stein Eye Institute, University of California, Los Angeles, Department of Ophthalmology, Los Angeles, California, United States of America aff001;  IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy aff002;  Columbia University, Department of Psychology, New York, New York, United States of America aff003;  Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy aff004;  University of Ottawa Eye Institute, Department of Ophthalmology, Ottawa, Ontario, Canada aff005;  The Huntington Medical Research Institutes and Molecular Neurology Program, Pasadena, California, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226197



Melanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body’s circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer’s disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD.


We performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid β42 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid β42 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm.


Our results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls.


The variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD.

Klíčová slova:

Alzheimer's disease – Circadian rhythms – Cognitive impairment – Chronobiology – Light – Retinal ganglion cells – Sleep


1. Koronyo Y, Biggs D, Barron E, Boyer DS, Pearlman JA, Au WJ, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. JCI Insight. 2017;2(16). Epub 2017/08/18. doi: 10.1172/jci.insight.93621 28814675; PubMed Central PMCID: PMC5621887.

2. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV, Miller CA, Ko MK, Black KL, et al. Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model. Neuroimage. 2011;54 Suppl 1:S204–17. Epub 2010/06/17. doi: 10.1016/j.neuroimage.2010.06.020 20550967; PubMed Central PMCID: PMC2991559.

3. Hart NJ, Koronyo Y, Black KL, Koronyo-Hamaoui M. Ocular indicators of Alzheimer's: exploring disease in the retina. Acta Neuropathol. 2016;132(6):767–87. Epub 2016/09/21. doi: 10.1007/s00401-016-1613-6 27645291; PubMed Central PMCID: PMC5106496.

4. Harrington MG, Chiang J, Pogoda JM, Gomez M, Thomas K, Marion SD, et al. Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study. PLoS One. 2013;8(11):e79378. Epub 2013/11/22. doi: 10.1371/journal.pone.0079378 24260210; PubMed Central PMCID: PMC3832547.

5. Sadun AA, Asanad S. The Eye in Alzheimer's Disease. Ophthalmology. 2019;126(4):511–2. Epub 2019/03/27. doi: 10.1016/j.ophtha.2018.10.001 30910035.

6. Lim JK, Li QX, He Z, Vingrys AJ, Wong VH, Currier N, et al. The Eye As a Biomarker for Alzheimer's Disease. Front Neurosci. 2016;10:536. Epub 2016/12/03. doi: 10.3389/fnins.2016.00536 27909396; PubMed Central PMCID: PMC5112261.

7. Asanad S, Ross-Cisneros FN, Nassisi M, Barron E, Karanjia R, Sadun AA. The Retina in Alzheimer's Disease: Histomorphometric Analysis of an Ophthalmologic Biomarker. Invest Ophthalmol Vis Sci. 2019;60(5):1491–500. Epub 2019/04/12. doi: 10.1167/iovs.18-25966 30973577.

8. La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G, et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol. 2016;79(1):90–109. Epub 2015/10/28. doi: 10.1002/ana.24548 26505992; PubMed Central PMCID: PMC4737313.

9. La Morgia C, Ross-Cisneros FN, Sadun AA, Carelli V. Retinal Ganglion Cells and Circadian Rhythms in Alzheimer's Disease, Parkinson's Disease, and Beyond. Front Neurol. 2017;8:162. Epub 2017/05/20. doi: 10.3389/fneur.2017.00162 28522986; PubMed Central PMCID: PMC5415575.

10. Coppola G, Di Renzo A, Ziccardi L, Martelli F, Fadda A, Manni G, et al. Optical Coherence Tomography in Alzheimer's Disease: A Meta-Analysis. PLoS One. 2015;10(8):e0134750. Epub 2015/08/08. doi: 10.1371/journal.pone.0134750 26252902; PubMed Central PMCID: PMC4529274.

11. den Haan J, Verbraak FD, Visser PJ, Bouwman FH. Retinal thickness in Alzheimer's disease: A systematic review and meta-analysis. Alzheimers Dement (Amst). 2017;6:162–70. Epub 2017/03/10. doi: 10.1016/j.dadm.2016.12.014 28275698; PubMed Central PMCID: PMC5328759.

12. Asanad S, Tian JJ, Frousiakis S, Jiang JP, Kogachi K, Felix CM, et al. Optical Coherence Tomography of the Retinal Ganglion Cell Complex in Leber's Hereditary Optic Neuropathy and Dominant Optic Atrophy. Curr Eye Res. 2019;44(6):638–44. Epub 2019/01/17. doi: 10.1080/02713683.2019.1567792 30649972.

13. Tales A, Troscianko T, Lush D, Haworth J, Wilcock GK, Butler SR. The pupillary light reflex in aging and Alzheimer's disease. Aging (Milano). 2001;13(6):473–8. Epub 2002/02/16. 11845975.

14. Schmidt TM, Chen SK, Hattar S. Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. Trends Neurosci. 2011;34(11):572–80. Epub 2011/08/06. doi: 10.1016/j.tins.2011.07.001 21816493; PubMed Central PMCID: PMC3200463.

15. Hannibal J, Hindersson P, Ostergaard J, Georg B, Heegaard S, Larsen PJ, et al. Melanopsin is expressed in PACAP-containing retinal ganglion cells of the human retinohypothalamic tract. Invest Ophthalmol Vis Sci. 2004;45(11):4202–9. Epub 2004/10/27. doi: 10.1167/iovs.04-0313 15505076.

16. Feng R, Li L, Yu H, Liu M, Zhao W. Melanopsin retinal ganglion cell loss and circadian dysfunction in Alzheimer's disease (Review). Mol Med Rep. 2016;13(4):3397–400. Epub 2016/03/05. doi: 10.3892/mmr.2016.4966 26935586; PubMed Central PMCID: PMC4805057.

17. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587–93. Epub 2013/03/13. doi: 10.1001/jamaneurol.2013.2334 23479184; PubMed Central PMCID: PMC3676720.

18. Peter-Derex L, Yammine P, Bastuji H, Croisile B. Sleep and Alzheimer's disease. Sleep Med Rev. 2015;19:29–38. Epub 2014/05/23. doi: 10.1016/j.smrv.2014.03.007 24846773.

19. La Morgia C, Carelli V, Carbonelli M. Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology. Front Neurol. 2018;9:1047. Epub 2018/12/26. doi: 10.3389/fneur.2018.01047 30581410; PubMed Central PMCID: PMC6292931.

20. Moura AL, Nagy BV, La Morgia C, Barboni P, Oliveira AG, Salomao SR, et al. The pupil light reflex in Leber's hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells. Invest Ophthalmol Vis Sci. 2013;54(7):4471–7. Epub 2013/06/06. doi: 10.1167/iovs.12-11137 23737476; PubMed Central PMCID: PMC4322722.

21. Park JC, Moura AL, Raza AS, Rhee DW, Kardon RH, Hood DC. Toward a clinical protocol for assessing rod, cone, and melanopsin contributions to the human pupil response. Invest Ophthalmol Vis Sci. 2011;52(9):6624–35. Epub 2011/07/12. doi: 10.1167/iovs.11-7586 21743008; PubMed Central PMCID: PMC3175993.

22. Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A. Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex. Ophthalmology. 2009;116(8):1564–73. Epub 2009/06/09. doi: 10.1016/j.ophtha.2009.02.007 19501408.

23. La Morgia C, Ross-Cisneros FN, Hannibal J, Montagna P, Sadun AA, Carelli V. Melanopsin-expressing retinal ganglion cells: implications for human diseases. Vision Res. 2011;51(2):296–302. Epub 2010/08/10. doi: 10.1016/j.visres.2010.07.023 20691201.

24. Chougule PS, Najjar RP, Finkelstein MT, Kandiah N, Milea D. Light-Induced Pupillary Responses in Alzheimer's Disease. Front Neurol. 2019;10:360. Epub 2019/04/30. doi: 10.3389/fneur.2019.00360 31031692; PubMed Central PMCID: PMC6473037.

25. Van Stavern GP, Bei L, Shui YB, Huecker J, Gordon M. Pupillary light reaction in preclinical Alzheimer's disease subjects compared with normal ageing controls. Br J Ophthalmol. 2019;103(7):971–5. Epub 2018/09/13. doi: 10.1136/bjophthalmol-2018-312425 30206156.

26. Frost S, Robinson L, Rowe CC, Ames D, Masters CL, Taddei K, et al. Evaluation of Cholinergic Deficiency in Preclinical Alzheimer's Disease Using Pupillometry. J Ophthalmol. 2017;2017:7935406. Epub 2017/09/13. doi: 10.1155/2017/7935406 28894607; PubMed Central PMCID: PMC5574262.

27. Fotiou D, Kaltsatou A, Tsiptsios D, Nakou M. Evaluation of the cholinergic hypothesis in Alzheimer's disease with neuropsychological methods. Aging Clin Exp Res. 2015;27(5):727–33. Epub 2015/03/10. doi: 10.1007/s40520-015-0321-8 25749905.

28. Rukmini AV, Milea D, Gooley JJ. Chromatic Pupillometry Methods for Assessing Photoreceptor Health in Retinal and Optic Nerve Diseases. Front Neurol. 2019;10:76. Epub 2019/02/28. doi: 10.3389/fneur.2019.00076 30809186; PubMed Central PMCID: PMC6379484.

29. Besser L, Kukull W, Knopman DS, Chui H, Galasko D, Weintraub S, et al. Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord. 2018;32(4):351–8. Epub 2018/10/31. doi: 10.1097/WAD.0000000000000279 30376508; PubMed Central PMCID: PMC6249084.

30. Witting W, Kwa IH, Eikelenboom P, Mirmiran M, Swaab DF. Alterations in the circadian rest-activity rhythm in aging and Alzheimer's disease. Biol Psychiatry. 1990;27(6):563–72. Epub 1990/03/15. doi: 10.1016/0006-3223(90)90523-5 2322616.

31. Lei S, Goltz HC, Chandrakumar M, Wong AM. Full-field chromatic pupillometry for the assessment of the postillumination pupil response driven by melanopsin-containing retinal ganglion cells. Invest Ophthalmol Vis Sci. 2014;55(7):4496–503. Epub 2014/06/14. doi: 10.1167/iovs.14-14103 24925879.

32. Li JY, Schmidt TM. Divergent projection patterns of M1 ipRGC subtypes. J Comp Neurol. 2018;526(13):2010–8. Epub 2018/06/12. doi: 10.1002/cne.24469 29888785; PubMed Central PMCID: PMC6158116.

33. Baver SB, Pickard GE, Sollars PJ, Pickard GE. Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus. Eur J Neurosci. 2008;27(7):1763–70. Epub 2008/03/29. doi: 10.1111/j.1460-9568.2008.06149.x 18371076.

34. Chen SK, Badea TC, Hattar S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature. 2011;476(7358):92–5. Epub 2011/07/19. doi: 10.1038/nature10206 21765429; PubMed Central PMCID: PMC3150726.

35. Esquiva G, Hannibal J. Melanopsin-expressing retinal ganglion cells in aging and disease. Histol Histopathol. 2019:18138. Epub 2019/06/21. doi: 10.14670/HH-18-138 31219170.

36. Reifler AN, Chervenak AP, Dolikian ME, Benenati BA, Meyers BS, Demertzis ZD, et al. The rat retina has five types of ganglion-cell photoreceptors. Exp Eye Res. 2015;130:17–28. Epub 2014/12/03. doi: 10.1016/j.exer.2014.11.010 25450063; PubMed Central PMCID: PMC4276437.

37. Quattrochi LE, Stabio ME, Kim I, Ilardi MC, Michelle Fogerson P, Leyrer ML, et al. The M6 cell: A small-field bistratified photosensitive retinal ganglion cell. J Comp Neurol. 2019;527(1):297–311. Epub 2018/10/13. doi: 10.1002/cne.24556 30311650; PubMed Central PMCID: PMC6594700.

38. Hannibal J, Christiansen AT, Heegaard S, Fahrenkrug J, Kiilgaard JF. Melanopsin expressing human retinal ganglion cells: Subtypes, distribution, and intraretinal connectivity. J Comp Neurol. 2017;525(8):1934–61. Epub 2017/02/06. doi: 10.1002/cne.24181 28160289.

39. Hannibal J, Kankipati L, Strang CE, Peterson BB, Dacey D, Gamlin PD. Central projections of intrinsically photosensitive retinal ganglion cells in the macaque monkey. J Comp Neurol. 2014;522(10):2231–48. Epub 2014/04/23. doi: 10.1002/cne.23588 24752373; PubMed Central PMCID: PMC3996456.

40. Esquiva G, Lax P, Perez-Santonja JJ, Garcia-Fernandez JM, Cuenca N. Loss of Melanopsin-Expressing Ganglion Cell Subtypes and Dendritic Degeneration in the Aging Human Retina. Front Aging Neurosci. 2017;9:79. Epub 2017/04/20. doi: 10.3389/fnagi.2017.00079 28420980; PubMed Central PMCID: PMC5378720.

41. Lax P, Ortuno-Lizaran I, Maneu V, Vidal-Sanz M, Cuenca N. Photosensitive Melanopsin-Containing Retinal Ganglion Cells in Health and Disease: Implications for Circadian Rhythms. Int J Mol Sci. 2019;20(13). Epub 2019/07/03. doi: 10.3390/ijms20133164 31261700.

42. Ortuno-Lizaran I, Esquiva G, Beach TG, Serrano GE, Adler CH, Lax P, et al. Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson's disease. Acta Neuropathol Commun. 2018;6(1):90. Epub 2018/09/12. doi: 10.1186/s40478-018-0596-z 30201049; PubMed Central PMCID: PMC6130068.

43. Camargos EF, Pandolfi MB, Dias MP, Quintas JL, Guimaraes RM, Nobrega Ode T. Incidence of sleep disorders in patients with Alzheimer disease. Einstein (Sao Paulo). 2011;9(4):461–5. Epub 2011/12/01. doi: 10.1590/S1679-45082011AO2145 26761246.

44. Hatfield CF, Herbert J, van Someren EJ, Hodges JR, Hastings MH. Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer's dementia. Brain. 2004;127(Pt 5):1061–74. Epub 2004/03/05. doi: 10.1093/brain/awh129 14998915.

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