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.

  • Review Article
  • Published:

The retina as a window to the brain—from eye research to CNS disorders

Abstract

Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.

Key Points

  • As an extension of the CNS, the retina displays similarities to the brain and spinal cord in terms of anatomy, functionality, response to insult, and immunology

  • Several major neurodegenerative disorders have manifestations in the retina, suggesting that the eye is a 'window' into the brain

  • Neurodegenerative processes that have been characterized in CNS disorders are also detected in some classic ocular pathologies

  • The accessibility and organization of the retina makes it a convenient research tool with which to study processes in the CNS

  • Advances in ocular imaging techniques support the potential of these approaches as effective aids in noninvasive diagnosis of CNS disorders

  • Future research should be aimed at testing whether therapies that are beneficial in brain disorders could also alleviate diseases of the eye, and vice versa

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The eye as an extension of the CNS.
Figure 2: Ocular manifestations of neurodegenerative disorders.

Similar content being viewed by others

References

  1. Dowling, J. E. in Encyclopedia of the Human Brain, Vol. 4 (ed. Ramachandran, V.) 217–235 (Academic Press, San Diego, 2002).

    Book  Google Scholar 

  2. Berson, D. M. in The Senses: A Comprehensive Reference, Vol. 1 (eds Basbaum, A. I. et al.) 491–519 (Elsevier, New York, 2008).

    Book  Google Scholar 

  3. Faden, A. I. & Salzman, S. Pharmacological strategies in CNS trauma. Trends Pharmacol. Sci. 13, 29–35 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Schwartz, M., Belkin, M., Yoles, E. & Solomon, A. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. J. Glaucoma 5, 427–432 (1996).

    CAS  PubMed  Google Scholar 

  5. Crowe, M. J., Bresnahan, J. C., Shuman, S. L., Masters, J. N. & Beattie, M. S. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat. Med. 3, 73–76 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Levkovitch-Verbin, H. et al. Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 42, 975–982 (2001).

    CAS  PubMed  Google Scholar 

  7. Levkovitch-Verbin, H. et al. A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection. Invest. Ophthalmol. Vis. Sci. 44, 3388–3393 (2003).

    Article  PubMed  Google Scholar 

  8. Yoles, E. & Schwartz, M. Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies. Exp. Neurol. 153, 1–7 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Benowitz, L. & Yin, Y. Rewiring the injured CNS: lessons from the optic nerve. Exp. Neurol. 209, 389–398 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Vidal-Sanz, M., Bray, G. M., Villegas-Perez, M. P., Thanos, S. & Aguayo, A. J. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J. Neurosci. 7, 2894–2909 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Keirstead, S. A. et al. Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science 246, 255–257 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Villegas-Perez, M. P., Vidal-Sanz, M., Bray, G. M. & Aguayo, A. J. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J. Neurosci. 8, 265–280 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Moalem, G. et al. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat. Med. 5, 49–55 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Kipnis, J. et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proc. Natl Acad. Sci. USA 97, 7446–7451 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lingor, P. et al. Inhibition of Rho kinase (ROCK) increases neurite outgrowth on chondroitin sulphate proteoglycan in vitro and axonal regeneration in the adult optic nerve in vivo. J. Neurochem. 103, 181–189 (2007).

    CAS  PubMed  Google Scholar 

  16. Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Lehmann, M. et al. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fischer, D., He, Z. & Benowitz, L. I. Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J. Neurosci. 24, 1646–1651 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5, 146–156 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Rolls, A. et al. Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med. 5, e171 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Filbin, M. T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat. Rev. Neurosci. 4, 703–713 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. David, S. & Aguayo, A. J. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214, 931–933 (1981).

    Article  CAS  PubMed  Google Scholar 

  23. Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat. Rev. Immunol. 3, 879–889 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Kaur, C., Foulds, W. S. & Ling, E. A. Blood–retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res. 27, 622–647 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Wilbanks, G. A. & Streilein, J. W. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-β. Eur. J. Immunol. 22, 1031–1036 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Taylor, A. W. & Streilein, J. W. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation 3, 112–118 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Cheung, N. et al. Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study. Brain 133, 1987–1993 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wong, T. Y. et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 358, 1134–1140 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Wong, T. Y. et al. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Surv. Ophthalmol. 46, 59–80 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Wong, T. Y. et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 288, 67–74 (2002).

    Article  PubMed  Google Scholar 

  31. Kalesnykas, G., Tuulos, T., Uusitalo, H. & Jolkkonen, J. Neurodegeneration and cellular stress in the retina and optic nerve in rat cerebral ischemia and hypoperfusion models. Neuroscience 155, 937–947 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Baker, M. L., Hand, P. J., Wang, J. J. & Wong, T. Y. Retinal signs and stroke: revisiting the link between the eye and brain. Stroke 39, 1371–1379 (2008).

    Article  PubMed  Google Scholar 

  33. Patton, N. et al. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J. Anat. 206, 319–348 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wardlaw, J. M. et al. Lacunar stroke is associated with diffuse blood–brain barrier dysfunction. Ann. Neurol. 65, 194–202 (2009).

    Article  PubMed  Google Scholar 

  35. Wardlaw, J. M., Sandercock, P. A., Dennis, M. S. & Starr, J. Is breakdown of the blood–brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34, 806–812 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Leibowitz, U. & Alter, M. Optic nerve involvement and diplopia as initial manifestations of multiple sclerosis. Acta Neurol. Scand. 44, 70–80 (1968).

    Article  CAS  PubMed  Google Scholar 

  37. McDonald, W. I. & Barnes, D. The ocular manifestations of multiple sclerosis. 1. Abnormalities of the afferent visual system. J. Neurol. Neurosurg. Psychiatry 55, 747–752 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sorensen, T. L., Frederiksen, J. L., Bronnum-Hansen, H. & Petersen, H. C. Optic neuritis as onset manifestation of multiple sclerosis: a nationwide, long-term survey. Neurology 53, 473–478 (1999).

    Article  CAS  PubMed  Google Scholar 

  39. Patel, S. J. & Lundy, D. C. Ocular manifestations of autoimmune disease. Am. Fam. Physician 66, 991–998 (2002).

    PubMed  Google Scholar 

  40. Soderstrom, M. Optic neuritis and multiple sclerosis. Acta Ophthalmol. Scand. 79, 223–227 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Ghezzi, A. et al. Long-term follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests. J. Neurol. 246, 770–775 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Firth, D. The case of Augustus d'Este (1794–1848): the first account of disseminated sclerosis: (Section of the History of Medicine). Proc. R. Soc. Med. 34, 381–384 (1941).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Fisher, J. B. et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 113, 324–332 (2006).

    Article  PubMed  Google Scholar 

  44. Monteiro, M. L., Fernandes, D. B., Apostolos-Pereira, S. L. & Callegaro, D. Quantification of retinal neural loss in patients with neuromyelitis optica and multiple sclerosis with or without optic neuritis using fourier-domain optical coherence tomography. Invest. Ophthalmol. Vis. Sci. 53, 3959–3966 (2012).

    Article  PubMed  Google Scholar 

  45. Green, A. J., McQuaid, S., Hauser, S. L., Allen, I. V. & Lyness, R. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain 133, 1591–1601 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kerrison, J. B., Flynn, T. & Green, W. R. Retinal pathologic changes in multiple sclerosis. Retina 14, 445–451 (1994).

    Article  CAS  PubMed  Google Scholar 

  47. Gundogan, F. C., Tas, A., Erdem, U. & Sobaci, G. Retinal pathology in multiple sclerosis: insight into the mechanisms of neuronal pathology. Brain 134, e171; author reply e172 (2011).

    Article  PubMed  Google Scholar 

  48. Masson, G., Mestre, D. & Blin, O. Dopaminergic modulation of visual sensitivity in man. Fundam. Clin. Pharmacol. 7, 449–463 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Santano, C., Pérez de Lara, M. & Pintor, J. in Studies on Experimental Models (eds Basu, S. & Wiklund, L.) 221–250 (Humana Press, New York, 2011).

    Book  Google Scholar 

  50. 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 

  51. Devos, D. et al. ERG and anatomical abnormalities suggesting retinopathy in dementia with Lewy bodies. Neurology 65, 1107–1110 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. 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 

  53. Inzelberg, R., Ramirez, J. A., Nisipeanu, P. & Ophir, A. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res. 44, 2793–2797 (2004).

    Article  PubMed  Google Scholar 

  54. 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 

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

    Article  PubMed  Google Scholar 

  56. Onofrj, M., Ghilardi, M. F., Basciani, M. & Gambi, D. Visual evoked potentials in parkinsonism and dopamine blockade reveal a stimulus-dependent dopamine function in humans. J. Neurol. Neurosurg. Psychiatry 49, 1150–1159 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chiu, K. et al. Neurodegeneration of the retina in mouse models of Alzheimer's disease: what can we learn from the retina? Age (Dordr.) 34, 633–649 (2012).

    Article  CAS  Google Scholar 

  58. Guo, L., Duggan, J. & Cordeiro, M. F. Alzheimer's disease and retinal neurodegeneration. Curr. Alzheimer Res. 7, 3–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Danesh-Meyer, H. V., Birch, H., Ku, J. Y., Carroll, S. & Gamble, G. Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging. Neurology 67, 1852–1854 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Hinton, D. R., Sadun, A. A., Blanks, J. C. & Miller, C. A. Optic-nerve degeneration in Alzheimer's disease. N. Engl. J. Med. 315, 485–487 (1986).

    Article  CAS  PubMed  Google Scholar 

  61. Blanks, J. C., Hinton, D. R., Sadun, A. A. & Miller, C. A. Retinal ganglion cell degeneration in Alzheimer's disease. Brain Res. 501, 364–372 (1989).

    Article  CAS  PubMed  Google Scholar 

  62. Blanks, J. C., Torigoe, Y., Hinton, D. R. & Blanks, R. H. Retinal pathology in Alzheimer's disease. I. Ganglion cell loss in foveal/parafoveal retina. Neurobiol. Aging 17, 377–384 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Blanks, J. C. et al. Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL. Neurobiol. Aging 17, 385–395 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Parisi, V. et al. Morphological and functional retinal impairment in Alzheimer's disease patients. Clin. Neurophysiol. 112, 1860–1867 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Berisha, F., Feke, G. T., Trempe, C. L., McMeel, J. W. & Schepens, C. L. Retinal abnormalities in early Alzheimer's disease. Invest. Ophthalmol. Vis. Sci. 48, 2285–2289 (2007).

    Article  PubMed  Google Scholar 

  66. Iseri, P. K., Altinas, O., Tokay, T. & Yuksel, N. Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. J. Neuroophthalmol. 26, 18–24 (2006).

    Article  PubMed  Google Scholar 

  67. Sadun, A. A. & Bassi, C. J. Optic nerve damage in Alzheimer's disease. Ophthalmology 97, 9–17 (1990).

    Article  CAS  PubMed  Google Scholar 

  68. Goldstein, L. E. et al. Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet 361, 1258–1265 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Ning, A., Cui, J., To, E., Ashe, K. H. & Matsubara, J. Amyloid-β deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest. Ophthalmol. Vis. Sci. 49, 5136–5143 (2008).

    Article  PubMed  Google Scholar 

  70. Liu, B. et al. Amyloid-peptide vaccinations reduce β-amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer's transgenic mice. Am. J. Pathol. 175, 2099–2110 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gasparini, L. et al. Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiol. Aging 32, 419–433 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Koronyo-Hamaoui, M. 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 54 (Suppl. 1), S204–S217 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Buggage, R. R., Chan, C. C. & Nussenblatt, R. B. Ocular manifestations of central nervous system lymphoma. Curr. Opin. Oncol. 13, 137–142 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Buckingham, B. P. et al. Progressive ganglion cell degeneration precedes neuronal loss in a mouse model of glaucoma. J. Neurosci. 28, 2735–2744 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Calkins, D. J. A neurological perspective on glaucoma. Glaucoma Today [online], (2008).

    Google Scholar 

  76. Jakobs, T. C., Libby, R. T., Ben, Y., John, S. W. & Masland, R. H. Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J. Cell Biol. 171, 313–325 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Braak, H. & Del Tredici, K. Nervous system pathology in sporadic Parkinson disease. Neurology 70, 1916–1925 (2008).

    Article  PubMed  Google Scholar 

  78. Selkoe, D. J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Fischer, L. R. & Glass, J. D. Axonal degeneration in motor neuron disease. Neurodegener. Dis. 4, 431–442 (2007).

    Article  PubMed  Google Scholar 

  80. Gupta, N. & Yucel, Y. H. Glaucoma as a neurodegenerative disease. Curr. Opin. Ophthalmol. 18, 110–114 (2007).

    Article  PubMed  Google Scholar 

  81. Yucel, Y. & Gupta, N. Glaucoma of the brain: a disease model for the study of transsynaptic neural degeneration. Prog. Brain Res. 173, 465–478 (2008).

    Article  PubMed  Google Scholar 

  82. Yin, H., Chen, L., Chen, X. & Liu, X. Soluble amyloid β oligomers may contribute to apoptosis of retinal ganglion cells in glaucoma. Med. Hypotheses 71, 77–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Janciauskiene, S. & Krakau, T. Alzheimer's peptide: a possible link between glaucoma, exfoliation syndrome and Alzheimer's disease. Acta Ophthalmol. Scand. 79, 328–329 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Yoneda, S. et al. Vitreous fluid levels of β-amyloid(1–42) and tau in patients with retinal diseases. Jpn J. Ophthalmol. 49, 106–108 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Gupta, N., Fong, J., Ang, L. C. & Yucel, Y. H. Retinal tau pathology in human glaucomas. Can. J. Ophthalmol. 43, 53–60 (2008).

    Article  PubMed  Google Scholar 

  86. Goldblum, D., Kipfer-Kauer, A., Sarra, G. M., Wolf, S. & Frueh, B. E. Distribution of amyloid precursor protein and amyloid-β immunoreactivity in DBA/2J glaucomatous mouse retinas. Invest. Ophthalmol. Vis. Sci. 48, 5085–5090 (2007).

    Article  PubMed  Google Scholar 

  87. Guo, L. et al. Targeting amyloid-β in glaucoma treatment. Proc. Natl Acad. Sci. USA 104, 13444–13449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Johnson, L. V. et al. The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc. Natl Acad. Sci. USA 99, 11830–11835 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dentchev, T., Milam, A. H., Lee, V. M., Trojanowski, J. Q. & Dunaief, J. L. Amyloid-β is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol. Vis. 9, 184–190 (2003).

    CAS  PubMed  Google Scholar 

  90. Yoshida, T. et al. The potential role of amyloid beta in the pathogenesis of age-related macular degeneration. J. Clin. Invest. 115, 2793–2800 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Isas, J. M. et al. Soluble and mature amyloid fibrils in drusen deposits. Invest. Ophthalmol. Vis. Sci. 51, 1304–1310 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Mullins, R. F., Russell, S. R., Anderson, D. H. & Hageman, G. S. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 14, 835–846 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Luibl, V. et al. Drusen deposits associated with aging and age-related macular degeneration contain nonfibrillar amyloid oligomers. J. Clin. Invest. 116, 378–385 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Klomp, L. W. & Gitlin, J. D. Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum. Mol. Genet. 5, 1989–1996 (1996).

    Article  CAS  PubMed  Google Scholar 

  95. Ke, Y. & Ming Qian, Z. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2, 246–253 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Hochstrasser, H. et al. Ceruloplasmin gene variations and substantia nigra hyperechogenicity in Parkinson disease. Neurology 63, 1912–1917 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Farkas, R. H. et al. Increased expression of iron-regulating genes in monkey and human glaucoma. Invest. Ophthalmol. Vis. Sci. 45, 1410–1417 (2004).

    Article  PubMed  Google Scholar 

  98. Levin, L. A. & Geszvain, K. M. Expression of ceruloplasmin in the retina: induction after optic nerve crush. Invest. Ophthalmol. Vis. Sci. 39, 157–163 (1998).

    CAS  PubMed  Google Scholar 

  99. Ishiura, H. et al. Posterior column ataxia with retinitis pigmentosa in a Japanese family with a novel mutation in FLVCR1. Neurogenetics 12, 117–121 (2011).

    Article  PubMed  Google Scholar 

  100. Rajadhyaksha, A. M. et al. Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am. J. Hum. Genet. 87, 643–654 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. London, A. et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J. Exp. Med. 208, 23–39 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Shechter, R. et al. Toll-like receptor 4 restricts retinal progenitor cell proliferation. J. Cell Biol. 183, 393–400 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yoles, E. et al. Protective autoimmunity is a physiological response to CNS trauma. J. Neurosci. 21, 3740–3748 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Anchan, R. M., Reh, T. A., Angello, J., Balliet, A. & Walker, M. EGF and TGF-α stimulate retinal neuroepithelial cell proliferation in vitro. Neuron 6, 923–936 (1991).

    Article  CAS  PubMed  Google Scholar 

  105. Yin, Y. et al. Oncomodulin links inflammation to optic nerve regeneration. Proc. Natl Acad. Sci. USA 106, 19587–19592 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zaverucha-do-Valle, C. et al. Bone marrow mononuclear cells increase retinal ganglion cell survival and axon regeneration in the adult rat. Cell Transplant. 20, 391–406 (2011).

    Article  PubMed  Google Scholar 

  107. Wong, T. Y. Is retinal photography useful in the measurement of stroke risk? Lancet Neurol. 3, 179–183 (2004).

    Article  PubMed  Google Scholar 

  108. De Silva, D. A. et al. Retinal microvascular changes and subsequent vascular events after ischemic stroke. Neurology 77, 896–903 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Frohman, E. M., Balcer, L. J. & Calabresi, P. A. Multiple sclerosis: can retinal imaging accurately detect optic neuritis? Nat. Rev. Neurol. 6, 125–126 (2010).

    Article  PubMed  Google Scholar 

  110. Naismith, R. T. et al. Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis. Neurology 73, 46–52 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Petzold, A. et al. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 9, 921–932 (2010).

    Article  PubMed  Google Scholar 

  112. Henderson, A. P. et al. An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography. Brain 131, 277–287 (2008).

    PubMed  Google Scholar 

  113. Gordon-Lipkin, E. et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 69, 1603–1609 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Grazioli, E. et al. Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis. J. Neurol. Sci. 268, 12–17 (2008).

    Article  PubMed  Google Scholar 

  115. Lennon, V. A. et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364, 2106–2112 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Ratchford, J. N. et al. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology 73, 302–308 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nakamura, M. et al. Early high-dose intravenous methylprednisolone is effective in preserving retinal nerve fiber layer thickness in patients with neuromyelitis optica. Graefes Arch. Clin. Exp. Ophthalmol. 248, 1777–1785 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Naismith, R. T. et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology 72, 1077–1082 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kesler, A., Vakhapova, V., Korczyn, A. D., Naftaliev, E. & Neudorfer, M. Retinal thickness in patients with mild cognitive impairment and Alzheimer's disease. Clin. Neurol. Neurosurg. 113, 523–526 (2011).

    Article  PubMed  Google Scholar 

  120. Paquet, C. et al. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer's disease. Neurosci. Lett. 420, 97–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Melnikova, I. Therapies for Alzheimer's disease. Nat. Rev. Drug Discov. 6, 341–342 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Ding, J. D. et al. Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration. Proc. Natl Acad. Sci. USA 108, E279–E287 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ding, J. D. et al. Targeting age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-β antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res. 48, 339–345 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Niikura, T., Hashimoto, Y., Tajima, H. & Nishimoto, I. Death and survival of neuronal cells exposed to Alzheimer's insults. J. Neurosci. Res. 70, 380–391 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Men, J., Zhang, X., Yang, Y. & Gao, D. An AD-related neuroprotector rescues transformed rat retinal ganglion cells from CoCl2-induced apoptosis. J. Mol. Neurosci. 47, 144–149 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Frenkel, D., Maron, R., Burt, D. S. & Weiner, H. L. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease. J. Clin. Invest. 115, 2423–2433 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Frenkel, D. et al. Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J. Immunol. 171, 6549–6555 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Ben Simon, G. J., Bakalash, S., Aloni, E. & Rosner, M. A rat model for acute rise in intraocular pressure: immune modulation as a therapeutic strategy. Am. J. Ophthalmol. 141, 1105–1111 (2006).

    Article  PubMed  Google Scholar 

  131. Schori, H. et al. Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: implications for glaucoma. Proc. Natl Acad. Sci. USA 98, 3398–3403 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mitne, S. et al. The potential neuroprotective effects of weekly treatment with glatiramer acetate in diabetic patients after panretinal photocoagulation. Clin. Ophthalmol. 5, 991–997 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  133. US National Library of Medicine. A randomized, double-blind, placebo-controlled, multicenter study of the effects of glatiramer acetate (GA) on the retinal nerve fiber layer (RNFL) and visual function in patients with a first episode of acute optic neuritis (AON). US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  134. US National Library of Medicine. Copaxone in age related macular degeneration. ClinicalTrials.gov[online], (2007).

  135. US National Library of Medicine. Weekly vaccination with copaxone as a potential therapy for dry age-related macular degeneration. ClinicalTrials.gov [online], (2008).

  136. Yucel, Y. H. et al. Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma. Arch. Ophthalmol. 124, 217–225 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. [No authors listed] Allergan reports fourth quarter operating results and announces restructuring. Allergan.com [online], (2008).

  138. Samples, J. R. in Ophthalmology Management (Wolters Kluwer Pharma Solutions Inc., Ambler, PA, 2011).

    Google Scholar 

  139. Wostyn, P., Audenaert, K. & De Deyn, P. P. Alzheimer's disease: cerebral glaucoma? Med. Hypotheses 74, 973–977 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Schwarzbaum for editorial assistance. The work of the authors is supported in part by The Glaucoma Foundation, the European Research Council Advanced Grant, and the FP7-HEALTH-2011 two-stage grant given to M. Schwartz.

Author information

Authors and Affiliations

Authors

Contributions

A. London and I. Benhar contributed equally to this manuscript. All authors contributed to researching data for the article, discussions of content, writing, and to the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Michal Schwartz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nrneurol.2012.227

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.227

This article is cited by

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