Publication: The Impact of the Eye in Dementia: The Eye and its Role in Diagnosis and Follow‐up
Loading...
Official URL
Full text at PDC
Publication Date
2016-09-28
Advisors (or tutors)
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Intech
Citations
Exportar
Abstract
Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. The retina is an extension of the CNS and thus should not be surprising to find abnormal results in both the test exploring visual processing and those examining the retina of patients with CNS degeneration. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of Alzheimer’s disease (AD) patients and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. In this chapter, we perform an analysis of the physiological changes in ocular and cerebral ageing. We analyse the ocular manifestations in CNS disorders such as stroke, AD and Parkinson’s disease. In addition, the pathophysiology of both the eye and the visual pathway in AD are described. The value of the visual psychophysical tests in AD diagnosis is reviewed as well as the main findings of the optical coherence tomography as a contribution to the diagnosis and monitoring of the disease. Finally, we examine the association of two neurodegenerative diseases, AD and glaucoma, as mere coincidence or possible role in the progression of the neurodegeneration.
Description
Open Access
UCM subjects
Unesco subjects
Keywords
Citation
[1] Jindal V. Interconnection between brain and retinal neurodegenerations. Molecular Neurobiology. 2014; 51: 1–8.
[2] Hirtz D, Thurman D, Gwinn‐Hardy K, Mohamed M, Chaudhuri A, Zalutsky R. How common are the “common” neurologic disorders? Neurology. 2007; 68: 326–337.
[3] Brookmeyer R, Johnson E, Ziegler‐Graham K, Arrighi HM. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s and Dementia. 2007; 3: 186–191.
[4] Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006; 368: 387–403.
[5] Cummings JL, Cole G. Alzheimer disease. JAMA. 2002; 287: 2335–2338.
[6] Small BJ, Gagnon E, Robinson B. Early identification of cognitive deficits: preclinical Alzheimer’s disease and mild cognitive impairment. Geriatrics. 2007; 62: 19–23.
[7] Ikram MK, Cheung CY, Wong TY, Chen CP. Retinal pathology as biomarker for cognitive impairment and Alzheimer’s disease. Journal of Neurology, Neurosurgery & Psychiatry. 2012; 83: 917–922.
[8] Hinton DR, Sadun AA, Blanks JC, Miller CA. Optic‐nerve degeneration in Alzheimer’s disease. The New England Journal of Medicine. 1986; 315: 485–487.
[9] Varma R, Bazzaz S, Lai M. Optical tomography–measured retinal nerve fiber layer thickness in normal Latinos. Investigative Ophthalmology & Visual Science. 2003; 44: 3369–3373.
[10] Paquet C, Boissonnot M, Roger F, Dighiero P, Gil R, Hugon J. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Neuroscience Letters. 2007; 420: 97–99.
[11] Cohen MJ, Kaliner E, Frenkel S, Kogan M, Miron H, Blumenthal EZ. Morphometric analysis of human peripapillary retinal nerve fiber layer thickness. Investigative Ophthalmology & Visual Science. 2008; 49: 941–944.
[12] Bowd C, Zangwill LM, Blumenthal EZ, Vasile C, Boehm AG, Gokhale PA, et al. Imaging of the optic disc and retinal nerve fiber layer: the effects of age, optic disc area, refractive error, and gender. Journal of the Optical Society of America A, Optics, Image Science, and Vision. 2002; 19: 197–207.
[13] Hedges III TR, Galves RP, Speigelman D, Barbas NR, Peli E, Yardley CJ. Retinal nerve fiber layer abnormalities in Alzheimer’s disease. Acta Ophthalmologica Scandinavica. 1996; 74: 271–275.
[14] Iseri PK, Altinas Ö, Tokay T, Yüksel N. Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease. Journal of Neuro‐ophthalmology. 2006; 26: 18–24.
[15] Berisha F, Feke GT, Trempe CL, McMeel JW, Schepens CL. Retinal abnormalities in early Alzheimer’s disease. Investigative Ophthalmology & Visual Science. 2007; 48: 2285–2289.
[16] Valenti DA. Neuroimaging of retinal nerve fiber layer in AD using optical coherence tomography. Neurology. 2007; 69: 1060.
[17] Kesler A, Vakhapova V, Korczyn AD, Naftaliev E, Neudorfer M. Retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Clinical Neurology and Neurosurgery. 2011; 113: 523–526.
[18] Moreno‐Ramos T, Benito‐León 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. Journal of Alzheimer’s Disease. 2013; 34: 659–664.
[19] Garcia‐Martin ES, Rojas B, Ramirez AI, de Hoz R, Salazar JJ, Yubero R, et al. Macular thickness as a potential biomarker of mild Alzheimer’s disease. Ophthalmology. 2014; 121: 1149–1151.
[20] Salobrar‐Garcia E, Hoyas I, Leal M, de Hoz R, Rojas B, Ramirez AI, et al. Analysis of retinal peripapillary segmentation in early Alzheimer’s disease patients. BioMed Research International. 2015; 2015: 636548.
[21] Blanks JC, Hinton DR, Sadun AA, Miller CA. Retinal ganglion cell degeneration in Alzheimer’s disease. Brain Research. 1989; 501: 364–372.
[22] Sadun A, Bassi C. Optic nerve damage in Alzheimer’s disease. Ophthalmology. 1990; 97: 9–17.
[23] Blanks JC, Torigoe Y, Hinton DR, Blanks RHI. Retinal pathology in Alzheimer’s disease. I. Ganglion cell loss in foveal/parafoveal retina. Neurobiology of Aging. 1996; 17: 377–384.
[24] Blanks JC, Schmidt SY, Torigoe Y, Porrello KV, Hinton DR, Blanks RH. Retinal pathology in Alzheimer’s disease. II. Regional neuron loss and glial changes in GCL. Neurobiology of Aging. 1996; 17: 385–395.
[25] Katz B, Rimmer S, Iragui V, Katzman R. Abnormal pattern electroretinogram in Alzheimer’s disease: evidence for retinal ganglion cell degeneration? Annals of Neurology. 1989; 26: 221–225.
[26] Trick GL, Barris MC, Bickler-Bluth M. Abnormal pattern electroretinograms in patients with senile dementia of the Alzheimer type. Annals of Neurology. 1989; 26: 226–231.
[27] Curcio CA, Drucker DN. Retinal ganglion cells in Alzheimer’s disease and aging. Annals of Neurology. 1993; 33: 248–257.
[28] Davies D, McCoubrie P, McDonald B, Jobst K. Myelinated axon number in the optic nerve is unaffected by Alzheimer’s disease. British Journal of Ophthalmology. 1995; 79: 596–600.
[29] Justino L, Kergoat M, Bergman H, Chertkow H, Robillard A, Kergoat H. Neuroretinal function is normal in early dementia of the Alzheimer type. Neurobiology of Aging. 2001; 22: 691–695.
[30] Kergoat H, Kergoat MJ, Justino L, Robillard A, Bergman H, Chertkow H. Normal optic nerve head topography in the early stages of dementia of the Alzheimer type. Dementia and Geriatric Cognitive Disorders. 2001; 12: 359–363.
[31] Kergoat H, Kergoat M, Justino L, Chertkow H, Robillard A, Bergman H. An evaluation of the retinal nerve fiber layer thickness by scanning laser polarimetry in individuals with dementia of the Alzheimer type. Acta Ophthalmologica Scandinavica. 2001; 79: 187–191.
[32] Kergoat Hln, Kergoat M, Justino L, Chertkow H, Robillard A, Bergman H. Visual retinocortical function in dementia of the Alzheimer type. Gerontology. 2002; 48: 197–203.
[33] Petersen R, Stevens J, Ganguli M, Tangalos E, Cummings J, DeKosky S. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence‐based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56: 1133–1142.
[34] Trick GL, Trick LR, Morris P, Wolf M. Visual field loss in senile dementia of the Alzheimer’s type. Neurology. 1995; 45: 68–74.
[35] Steffes R, Thralow J. Visual field limitation in the patient with dementia of the Alzheimer’s type. Journal of the American Geriatrics Society. 1987; 35:198–204.
[36] Risacher SL, WuDunn D, Pepin SM, MaGee TR, McDonald BC, Flashman LA, et al. Visual contrast sensitivity in Alzheimer’s disease, mild cognitive impairment, and older adults with cognitive complaints. Neurobiology of Aging. 2013; 34: 1133–1144.
[37] Cronin‐Golomb A, Sugiura R, Corkin S, Growdon JH. Incomplete achromatopsia in Alzheimer’s disease. Neurobiology of Aging. 1993; 14: 471–477.
[38] Pache M, Smeets CH, Gasio PF, Savaskan E, Flammer J, Wirz-Justice A, et al. Colour vision deficiencies in Alzheimer’s disease. Age and Ageing. 2003; 32: 422–426.
[39] Salamone G, Di Lorenzo C, Mosti S, Lupo F, Cravello L, Palmer K, et al. Color discrimination performance in patients with Alzheimer’s disease. Dementia and Geriatric Cognitive Disorders. 2009; 27: 501–507.
[40] Salobrar‐Garcia E, de Hoz R, Rojas B, Ramirez AI, Salazar JJ, Yubero R, et al. Ophthalmologic psychophysical tests support OCT findings in mild Alzheimer’s disease. Journal of Ophthalmology. 2015; Article ID 736949.
[41] Krasodomska K, Lubiński W, Potemkowski A, Honczarenko K. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) in the early stages of Alzheimer’s disease. Documenta Ophthalmologica. 2010; 121: 111–121.
[42] Parisi V, Restuccia R, Fattapposta F, Mina C, Bucci MG, Pierelli F. Morphological and functional retinal impairment in Alzheimer’s disease patients. Clinical Neurophysiology. 2001; 112: 1860–1867.
[43] Cronin‐Golomb A, Rizzo J, Corkin S, Growdon J. Visual function in Alzheimer’s disease and normal aging. Annals of the New York Academy of Sciences. 1991; 640: 28–35.
[44] Lakshminarayanan V, Lagrave J, Kean ML, Dick M, Shankle R. Vision in dementia: contrast effects. Neurological Research. 1996; 18: 9–15.
[45] Neargarder SA, Stone ER, Cronin‐Golomb A, Oross S. The impact of acuity on performance of four clinical measures of contrast sensitivity in Alzheimer’s disease. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences. 2003; 58: P54–P62.
[46] Valenti DA. Alzheimer’s disease: visual system review. Optometry. 2010; 81: 12–21.
[47] Tzekov RT, Mullan M. Vision function abnormalities in Alzheimer’s disease. Survey of Ophthalmology. 2013; 59: 414–433.
[48] Schlotterer G, Moscovitch M, Crapper‐McLachlan D. Visual processing deficits as assessed by spatial frequency contrast sensitivity and backward masking in normal ageing and Alzheimer’s disease. Brain: A Journal of Neurology. 1984; 107: 309–325.
[49] Wright CE, Drasdo N, Harding GF. Pathology of the optic nerve and visual association areas information given by the flash and pattern visual evoked potential, and the temporal and spatial contrast sensitivity function. Brain. 1987; 110: 107–120.
[50] Cronin‐Golomb A, Corkin S, Growdon JH. Contrast sensitivity in Alzheimer’s disease. Journal of the Optical Society of America A, Optics, Image Science, and Vision. 1987; 4: 7.
[51] Morris JC. Mild cognitive impairment and preclinical Alzheimer’s disease. Geriatrics. 2005; Suppl: 9–14.
[52] Inzelberg R, Ramirez JA, Nisipeanu P, Ophir A. Retinal nerve fiber layer thinning in Parkinson disease. Vision Research. 2004; 44: 2793–2797.
[53] Altintas Ö, Iseri P, Özkan B, Çağlar Y. Correlation between retinal morphological and functional findings and clinical severity in Parkinson’s disease. Documenta Ophthalmologica. 2008; 116: 137–146.
[54] Burkholder BM, Osborne B, Loguidice MJ, Bisker E, Frohman TC, Conger A, et al. Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. Archives of Neurology. 2009; 66: 1366–1372.
[55] Aaker GD, Myung JS, Ehrlich JR, Mohammed M, Henchcliffe C, Kiss S. Detection of retinal changes in Parkinson’s disease with spectral‐domain optical coherence tomography. Clinical Ophthalmology. 2010; 4: 1427–1432.
[56] Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging‐Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s and Dementia. 2011; 7: 270–279.
[57] Bodis‐Wollner I. Foveal vision is impaired in Parkinson’s disease. Parkinsonism & Related Disorders. 2012; 19: 1–14.
[58] La Morgia C, Barboni P, Rizzo G, Carbonelli M, Savini G, Scaglione C, et al. Loss of temporal retinal nerve fibers in Parkinson disease: a mitochondrial pattern? European Journal of Neurology. 2012; 20: 198–201.
[59] Spund B, Ding Y, Liu T, Selesnick I, Glazman S, Shrier E, et al. Remodeling of the fovea in Parkinson disease. Journal of Neural Transmission. 2013; 120: 745–753.
[60] Tátrai E, Simó M, Iljicsov A, Németh J, DeBuc DC, Somfai GM. In vivo evaluation of retinal neurodegeneration in patients with multiple sclerosis. PLoS ONE. 2012; 7: e30922.
[61] Satue M, Garcia‐Martin E, Fuertes I, Otin S, Alarcia R, Herrero R, et al. Use of Fourier‐domain OCT to detect retinal nerve fiber layer degeneration in Parkinson’s disease patients. Eye. 2013; 27: 507–514.
[62] Gao L, Liu Y, Li X, Bai Q, Liu P. Abnormal retinal nerve fiber layer thickness and macula lutea in patients with mild cognitive impairment and Alzheimer’s disease. Archives of Gerontology and Geriatrics. 2015; 60: 162–167.
[63] Marziani E, Pomati S, Ramolfo P, Cigada M, Giani A, Mariani C, et al. Evaluation of retinal nerve fiber layer and ganglion cell layer thickness in Alzheimer’s disease using spectral‐domain optical coherence tomography. Investigative Ophthalmology & Visual Science. 2013; 54: 5953–5958.
[64] Maldonado RS, Mettu P, El‐Dairi M, Bhatti MT. The application of optical coherence tomography in neurologic diseases. Neurology: Clinical Practice. 2015; 5: 460–469.
[65] Millán Calenti JC. Gerontology and Geriatrics: assessment and intervention. Madrid; Médica Panamericana. 2010; 708.
[66] López‐Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153: 1194–1217.
[67] Oh SR, Chokthaweesak W, Annunziata CC, Priel A, Korn BS, Kikkawa DO. Analysis of eyelid fat pad changes with aging. Ophthalmic Plastic & Reconstructive Surgery. 2011; 27: 348–351.
[68] Shore JW. Changes in lower eyelid resting position, movement, and tone with age. American Journal of Ophthalmology. 1985; 99: 415–423.
[69] Van Haeringen N. Aging and the lacrimal system. British Journal of Ophthalmology. 1997; 81: 824–826.
[70] Zhu W, Hong J, Zheng T, Le Q, Xu J, Sun X. Age‐related changes of human conjunctiva on in vivo confocal microscopy. British Journal of Ophthalmology. 2010; 94: 1448–1453.
[71] Rada JA, Achen VR, Penugonda S, Schmidt RW, Mount BA. Proteoglycan composition in the human sclera during growth and aging. Investigative Ophthalmology & Visual Science. 2000; 41: 1639–1648.
[72] Grossniklaus HE, Nickerson JM, Edelhauser HF, Bergman LA, Berglin L. Anatomic alterations in aging and age‐related diseases of the eye. Investigative Ophthalmology & Visual Science. 2013; 54: ORSF23–ORSF27.
[73] Faragher R, Mulholland B, Tuft S, Sandeman S, Khaw P. Aging and the cornea. British Journal of Ophthalmology. 1997; 81: 814–817.
[74] Gipson IK. Age‐related changes and diseases of the ocular surface and cornea. Investigative Ophthalmology & Visual Science. 2013; 54: ORSF48–ORSF53.
[75] McMenamin PG, Lee WR, Aitken DA. Age‐related changes in the human outflow apparatus. Ophthalmology. 1986; 93: 194–209.
[76] Salvi S, Akhtar S, Currie Z. Ageing changes in the eye. Postgraduate Medical Journal. 2006; 82: 581–587.
[77] Birren JE, Casperson RC, Botwinick J. Age changes in pupil size. Journal of Gerontology. 1950; 5: 216–221.
[78] Barteselli G, Chhablani J, El‐Emam S, Wang H, Chuang J, Kozak I, et al. Choroidal volume variations with age, axial length, and sex in healthy subjects: a three‐dimensional analysis. Ophthalmology. 2012;119: 2572–2578.
[79] Ramrattan RS, van der Schaft, Theo L, Mooy CM, De Bruijn W, Mulder P, De Jong P. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Investigative Ophthalmology & Visual Science. 1994; 35: 2857–2864.
[80] Pauleikhoff D, Harper CA, Marshall J, Bird AC. Aging changes in Bruch’s membrane: a histochemical and morphologic study. Ophthalmology. 1990; 97: 171–178.
[81] Newsome DA, Huh W, Green WR. Bruch’s membrane age‐related changes vary by region. Current Eye Research. 1987; 6: 1211–1221.
[82] Ramírez JM, Ramírez AI, Salazar JJ, de Hoz R, Triviño A. Changes of astrocytes in retinal ageing and age‐related macular degeneration. Experimental Eye Research. 2001; 73: 601–615.
[83] Grunwald JE, Piltz J, Patel N, Bose S, Riva CE. Effect of aging on retinal macular microcirculation: a blue field simulation study. Investigative Ophthalmology & Visual Science. 1993; 34: 3609–3613.
[84] Moya FJ, Brigatti L, Caprioli J. Effect of aging on optic nerve appearance: a longitudinal study. British Journal of Ophthalmology. 1999; 83: 567–572.
[85] Sebag J. Ageing of the vitreous. Eye. 1987; 1: 254–262.
[86] Dagnelie G. Age‐Related Psychophysical Changes and Low Vision. Investigative Ophthalmology & Visual Science. 2013; 54: ORSF88–ORSF93.
[87] Haegerstrom‐Portnoy G, Schneck ME, Brabyn JA, Lott LA. Development of refractive errors into old age. Optometry & Vision Science. 2002; 79: 643–649.
[88] Derefeldt G, Lennerstrand G, Lundh B. Age variations in normal human contrast sensitivity. Acta Ophthalmologica. 1979; 57: 679–690.
[89] Leat SJ, Chan LL, Maharaj P, Hrynchak PK, Mittelstaedt A, Machan CM, et al. Binocular vision and eye movement disorders in older adults. Investigative Ophthalmology & Visual Science. 2013; 54: 3798–3805.
[90] Reuter‐Lorenz PA. New visions of the aging mind and brain. Trends in Cognitive Sciences. 2002; 6: 394–400.
[91] Creasey H, Rapoport SI. The aging human brain. Annals of Neurology. 1985; 17: 2–10.
[92] Masliah E, Mallory M, Hansen L, DeTeresa R, Terry R. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology. 1993; 43: 192.
[93] Hof PR, Morrison JH. The aging brain: morphomolecular senescence of cortical circuits. Trends in Neurosciences. 2004; 27: 607–613.
[94] Hedden T, Gabrieli JDE. Insights into the ageing mind: a view from cognitive neuroscience. Nature Reviews Neuroscience. 2004; 5: 87–96.
[95] Pappolla M, Omar R, Saran B. The “normal” brain.” Abnormal ubiquitinilated deposits highlight an age‐related protein change. American Journal of Pathology. 1989; 135: 585–591.
[96] Nakano M, Oenzil F, Mizuno T, Gotoh S. Age‐related changes in the lipofuscin accumulation of brain and heart. Gerontology. 1995; 41: 69–80.
[97] Coria F, Moreno A, Rubio I, Garcia M, Morato E. The cellular pathology associated with Alzheimer β-amyloid deposits in non-demented aged individuals. Neuropathology and Applied Neurobiology. 1993; 19: 261–268.
[98] Morris JC, McKeel Jr D, Storandt M, Rubin E, Price J, Grant E, et al. Very mild Alzheimer’s disease Informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991; 41: 469–478.
[99] Boone KB, Miller BL, Lesser IM, Mehringer CM, Hill‐Gutierrez E, Goldberg MA, et al. Neuropsychological correlates of white‐matter lesions in healthy elderly subjects: a threshold effect. Archives of Neurology. 1992; 49: 549–554.
[100] Zerfass R, Geiger‐Kabisch C, Sattel H, Besthorn C, Hentschel F. Brain atrophy in normal ageing and Alzheimer’s disease. Volumetric discrimination and clinical correlations. British Journal of Psychiatry. 1995; 167: 739–746.
[101] Reed BR, Eberling JL, Mungas D, Weiner M, Kramer JH, Jagust WJ. Effects of white matter lesions and lacunes on cortical function. Archives of Neurology. 2004; 61: 1545–1550.
[102] O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurology. 2003; 2: 89–98.
[103] Fratiglioni L, Mangialasche F, Qiu C. Brain aging: lessons from community studies. Nutrition Reviews. 2010; 68: S119–S127.
[104] Grammas P, Martinez J, Miller B. Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. Expert Reviews in Molecular Medicine. 2011; 13: e19.
[105] Mrak RE, Griffin S, Graham DI. Aging‐associated changes in human brain. Journal of Neuropathology and Experimental Neurology. 1997; 56: 1269–1275.
[106] Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, et al. Protective role of reactive astrocytes in brain ischemia. Journal of Cerebral Blood Flow & Metabolism. 2007; 28: 468–481.
[107] Frith CD, Frith U. Implicit and explicit processes in social cognition. Neuron. 2008; 60: 503–510.
[108] Sander M, Bergersen LH, Storm‐Mathisen J. Molecular approaches to understanding neural network plasticity and memory: the Kavli Prize Inaugural Symposium on Neuroscience. Neuroscience. 2009; 163: 965–976.
[109] Dámaso S, Viadero C. Normal and Pathological changes in aging brain. Revista Neuropsicología, Neuropsiquiatría y Neurociencias. 2012; 12: 21–36.
[110] Bliss TVP, Lømo T. Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. Journal of Physiology. 1973; 232: 331–356.
[111] Alvarez VA, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. Annual Review of Neuroscience. 2007; 30: 79–97.
[112] VanGuilder HD, Farley JA, Yan H, Van Kirk CA, Mitschelen M, Sonntag WE, et al. Hippocampal dysregulation of synaptic plasticity‐associated proteins with age‐related cognitive decline. Neurobiology of Disease. 2011; 43: 201–212.
[113] Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behavioural Brain Research. 2011; 221: 555–563.
[114] London A, Benhar I, Schwartz M. The retina as a window to the brain‐from eye research to CNS disorders. Nature Reviews Neurology. 2013; 9: 44–53.
[115] Ramachandran VS. Encyclopedia of the Human Brain. Academic Press; 2002.
[116] Faden AI, Salzman S. Pharmacological strategies in CNS trauma. Trends in Pharmacological Sciences. 1992; 13: 29–35.
[117] Schwartz M, Belkin M, Yoles E, Solomon A. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. Journal of Glaucoma. 1996; 5: 427–432.
[118] Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Crowe MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nature Medicine. 1997; 3: 73–76.
[119] Yoles E, Schwartz M. Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies. Experimental Neurology. 1998; 153: 1–7.
[120] Levkovitch–Verbin H, Quigley HA, Kerrigan–Baumrind LA, D’Anna SA, Kerrigan D, Pease ME. Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells. Investigative Ophthalmology & Visual Science. 2001; 42: 975–982.
[121] Levkovitch‐Verbin H, Quigley HA, Martin KR, Zack DJ, Pease ME, Valenta DF. A model to study differences between primary and secondary degeneration of retinal ganglion cells in rats by partial optic nerve transection. Investigative Ophthalmology & Visual Science. 2003; 44: 3388–3393.
[122] Vidal‐Sanz M, Bray GM, Villegas‐Perez M, Thanos S, Aguayo AJ. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. Journal of Neuroscience. 1987; 7: 2894–2909.
[123] Villegas‐Perez M, Vidal‐Sanz M, Bray GM, Aguayo AJ. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. Journal of Neuroscience. 1988; 8: 265–280.
[124] Keirstead S, Rasminsky M, Fukuda Y, Carter D, Aguayo A, Vidal‐Sanz M. Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science. 1989; 246: 255–257.
[125] Moalem G, Leibowitz–Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nature Medicine. 1999; 5: 49–55.
[126] Kipnis J, Yoles E, Porat Z, Cohen A, Mor F, Sela M, et al. T cell immunity to copolymer 1 confers neuroprotection on the damaged optic nerve: possible therapy for optic neuropathies. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97: 7446–7451.
[127] Lingor P, Teusch N, Schwarz K, Mueller R, Mack H, Bähr M, et al. Inhibition of Rhokinase (ROCK) increases neurite outgrowth on chondroitin sulphate proteoglycan in vitro and axonal regeneration in the adult optic nerve in vivo. Journal of Neurochemistry. 2007; 103: 181–189.
[128] Benowitz L, Yin Y. Rewiring the injured CNS: lessons from the optic nerve. Experimental Neurology. 2008; 209: 389–398.
[129] David S, Aguayo AJ. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science. 1981; 214: 931–933.
[130] Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nature Reviews Immunology. 2003; 3: 879–889.
[131] Kaur C, Foulds W, Ling E. Blood–retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Progress in Retinal and Eye Research. 2008; 27: 622–647.
[132] Wilbanks GA, Wayne Streilein J. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-β. European Journal of Immunology. 1992; 22: 1031–1036.
[133] Taylor A, Streilein J. Inhibition of antigen‐stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation. 1996; 3: 112–118.
[134] Nassi JJ, Callaway EM. Parallel processing strategies of the primate visual system. Nature Reviews Neuroscience. 2009; 10: 360–372.
[135] Mandal PK, Joshi J, Saharan S. Visuospatial perception: an emerging biomarker for Alzheimer’s disease. Journal of Alzheimer’s Disease. 2012; 31: 117–135.
[136] Livingstone MS, Hubel DH. Psychophysical evidence for separate channels for the perception of form, color, movement, and depth. Journal of Neuroscience. 1987; 7: 3416–3468.
[137] Maunsell JH, Newsome WT. Visual processing in monkey extrastriate cortex. Annual Review of Neuroscience. 1987; 10: 363–401.
[138] Chatterjee S, Callaway EM. Parallel colour‐opponent pathways to primary visual cortex. Nature. 2003; 426: 668–671.
[139] Roe AW, Ts’o DY. Visual topography in primate V2: multiple representation across functional stripes. The Journal of Neuroscience. 1995; 15: 3689–3715.
[140] Braddick OJ, O’Brien JM, Wattam‐Bell J, Atkinson J, Hartley T, Turner R. Brain areas sensitive to coherent visual motion. Perception‐London. 2001; 30: 61–72.
[141] Possin KL. Visual spatial cognition in neurodegenerative disease. Neurocase. 2010; 16: 466–487.
[142] Zeki S. The disunity of consciousness. Progress in Brain Research. 2007; 168: 11–268.
[143] Cheung N, Mosley T, Islam A, Kawasaki R, Sharrett AR, Klein R, et al. Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: a prospective study. Brain. 2010; 133: 1987–1993.
[144] Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao D, et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002; 288: 67–74.
[145] Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet. 2001; 358: 1134–1140.
[146] Wong TY, Klein R, Klein BE, Tielsch JM, Hubbard L, Nieto FJ. Retinal microvascular abnormalities and their relationship with hypertension, cardiovascular disease, and mortality. Survey of Ophthalmology. 2001; 46: 59–80.
[147] 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. 2008; 155: 937–947.
[148] Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ, Dhillon B. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. Journal of Anatomy. 2005; 206: 319–348.
[149] Baker ML, Hand PJ, Wang JJ, Wong TY. Retinal signs and stroke: revisiting the link between the eye and brain. Stroke. 2008; 39: 1371–1379.
[150] London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S, et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte‐derived macrophages. Journal of Experimental Medicine. 2011; 208: 23–39.
[151] Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Muñoz Maniega S, et al. Lacunar stroke is associated with diffuse blood–brain barrier dysfunction. Annals of Neurology. 2009; 65: 194–202.
[152] Leibowitz U, Alter M. Optic nerve involvement and diplopia as initial manifestations of multiple sclerosis. Acta Neurologica Scandinavica. 1968; 44: 70–80.
[153] McDonald W, Barnes D. The ocular manifestations of multiple sclerosis. 1. Abnormalities of the afferent visual system. Journal of Neurology, Neurosurgery, and Psychiatry. 1992; 55: 747–752.
[154] Sørensen T, Frederiksen J, Brønnum‐Hansen H, Petersen H. Optic neuritis as onset manifestation of multiple sclerosis: a nationwide, long‐term survey. Neurology. 1999; 53: 473–473.
[155] Patel SJ, Lundy DC. Ocular manifestations of autoimmune disease. American Family Physician. 2002; 66: 991–998.
[156] Gundogan FC, Tas A, Erdem U, Sobaci G. Retinal pathology in multiple sclerosis: insight into the mechanisms of neuronal pathology. Brain: A Journal of Neurology. 2011; 134: 1–2 /e171.
[157] Ghezzi A, Martinelli V, Torri V, Zaffaroni M, Rodegher M, Comi G, 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. Journal of Neurology. 1999; 246: 770–775.
[158] Regan D, Silver R, Murray TJ. Visual acuity and contrast sensitivity in multiple sclerosis – hidden visual loss: an auxiliary diagnostic test. Brain: A Journal of Neurology. 1977; 100: 563–579.
[159] Balcer L, Baier M, Cohen J, Kooijmans M, Sandrock A, Nano‐Schiavi M, et al. Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology. 2003; 61: 1367–1373.
[160] Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology. 2007; 68: 288–291.
[161] Monteiro ML, Fernandes DB, Apóstolos‐Pereira SL, Callegaro D. Quantification of retinal neural loss in patients with neuromyelitis optical and multiple sclerosis with or without optic neuritis using Fourier‐domain optical coherence tomography. Investigative Ophthalmology & Visual Science. 2012; 53: 3959–3966.
[162] Frohman E, Costello F, Zivadinov R, Stuve O, Conger A, Winslow H, et al. Optical coherence tomography in multiple sclerosis. Lancet Neurology. 2006; 5: 853–863.
[163] Zaveri MS, Conger A, Salter A, Frohman TC, Galetta SL, Markowitz CE, et al. Retinal imaging by laser polarimetry and optical coherence tomography evidence of axonal degeneration in multiple sclerosis. Archives of Neurology. 2008; 65: 924–928.
[164] Adam CR, Shrier E, Ding Y, Glazman S, Bodis‐Wollner I. Correlation of inner retinal thickness evaluated by spectral‐domain optical coherence tomography and contrast sensitivity in Parkinson disease. Journal of Neuro‐ophthalmology. 2013; 33: 137–142.
[165] Masson G, Mestre D, Blin O. Dopaminergic modulation of visual sensitivity in man. Fundamental & Clinical pharmacology. 1993; 7: 449–463.
[166] Moschos MM, Tagaris G, Markopoulos I, Margetis I, Tsapakis S, Kanakis M, et al. Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. European Journal of Ophthalmology. 2011; 21: 24–29.
[167] Yu J, Feng Y, Xiang Y, Huang J, Savini G, Parisi V, et al. Retinal nerve fiber layer thickness changes in Parkinson disease: a meta‐analysis. PLoS One. 2014; 9: e85718.
[168] Onofrj M, Ghilardi M, Basciani M, Gambi D. Visual evoked potentials in parkinsonism and dopamine blockade reveal a stimulus‐dependent dopamine function in humans. Journal of Neurology, Neurosurgery & Psychiatry. 1986; 49: 1150–1159.
[169] Mapstone M, Dickerson K, Duffy CJ. Distinct mechanisms of impairment in cognitive ageing and Alzheimer’s disease. Brain : A Journal of Neurology. 2008; 131: 1618–1629.
[170] Prvulovic D, Hubl D, Sack A, Melillo L, Maurer K, Frölich L, et al. Functional imaging of visuospatial processing in Alzheimer’s disease. NeuroImage. 2002; 17: 1403–1414.
[171] Rizzo M, Anderson SW, Dawson J, Nawrot M. Vision and cognition in Alzheimer’s disease. Neuropsychologia. 2000; 38: 1157–1169.
[172] Tippett WJ, Black SE. Regional cerebral blood flow correlates of visuospatial tasks in Alzheimer’s disease. Journal of the International Neuropsychological Society. 2008; 14: 1034–1045.
[173] Kurylo DD, Corkin S, Dolan RP, Rizzo JF, Parker SW, Growdon JH. Broad‐band visual capacities are not selectively impaired in Alzheimer’s disease. Neurobiology of Aging. 1994; 15: 305–311.
[174] Rizzo M, Anderson S, Dawson J, Myers R, Ball K. Visual attention impairments in Alzheimer’s disease. Neurology. 2000; 54: 1954–1959.
[175] Holroyd S, Shepherd ML. Alzheimer’s disease: a review for the ophthalmologist. Survey of Ophthalmology. 2001; 45: 516–524.
[176] Jackson GR, Owsley C. Visual dysfunction, neurodegenerative diseases, and aging. Neurologic Clinics. 2003; 21: 709–728.
[177] Cummings JL. Alzheimer’s disease. The New England Journal of Medicine. 2004; 351: 56–67.
[178] Denise A. V. Alzheimer’s disease: visual system review. Optometry. 2010; 81: 12–21.
[179] Frost S, Martins RN, Kanagasingam Y. Ocular biomarkers for early detection of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2010; 22: 1–16.
[180] Kirby E, Bandelow S, Hogervorst E. Visual impairment in Alzheimer’s disease: a critical review. Journal of Alzheimer’s Disease. 2010; 21: 15–34.
[181] Chiu K, Chan T, Wu A, Leung IY, So K, Chang RC. Neurodegeneration of the retina in mouse models of Alzheimer’s disease: what can we learn from the retina? Age. 2012; 34: 633–649.
[182] Chiu K, So K, Chang RC. Progressive neurodegeneration of retina in Alzheimer’s disease—are β‐amyloid peptide and tau new pathological factors in glaucoma? In: Rumelt S, editor. Glaucoma – basic and clinical aspects. InTech; 2013. p. 157–177.
[183] Sivak JM. The aging eye: common degenerative mechanisms between the Alzheimer’s brain and retinal disease. Investigative Ophthalmology & Visual Science. 2013; 54: 871–880.
[184] Ong Y, Ong Y, Ikram MK, Chen CLH, Wong TY, Cheung CY. Potential applications of Spectral‐Domain Optical Coherence Tomography (SD‐OCT) in the study of Alzheimer’s Disease. Proceedings of Singapore Healthcare. 2014; 23: 74–83.
[185] Dehabadi MH, Davis BM, Wong TK, Cordeiro MF. Retinal manifestations of Alzheimer’s disease. Neurodegenerative Disease Management. 2014; 4: 241–252.
[186] Thomson KL, Yeo JM, Waddell B, Cameron JR, Pal S. A systematic review and metaanalysis of retinal nerve fiber layer change in dementia, using optical coherence tomography. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2015; 1: 136–143.
[187] Kopishinskaya S, Svetozarskiy S. Retinal optical coherence tomography in neurodegenerative diseases (review). Sovremennye Tehnologii v Medicine. 2015; 7: 116–123.
[188] Parnell M, Guo L, Abdi M, Cordeiro MF. Ocular manifestations of Alzheimer’s disease in animal models. International Journal of Alzheimer’s Disease. 2012; 2012: 786494.
[189] Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X, et al. Cytosolic β‐amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer’s disease. Lancet. 2003; 361: 1258–1265.
[190] Bei L, Shui Y, Bai F, Nelson SK, Van Stavern GP, Beebe DC. A test of lens opacity as an indicator of preclinical Alzheimer Disease. Experimental Eye Research. 2015; 140: 117–123.
[191] Tsai Y, Lu B, Ljubimov AV, Girman S, Ross‐Cisneros FN, Sadun AA, et al. Ocular changes in TgF344‐AD rat model of Alzheimer’s disease. Investigative Ophthalmology & Visual Science. 2014; 55: 523–534.
[192] Frost S, Kanagasingam Y, Sohrabi H, Vignarajan J, Bourgeat P, Salvado O, et al. Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease. Translational Psychiatry. 2013; 3: e233.
[193] de la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke. 2002; 33: 1152–1162.
[194] Bell RD, Zlokovic BV. Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease. Acta Neuropathologica. 2009; 118: 103–113.
[195] Mroczkowska S, Benavente‐Perez A, Patel S, Qin L, Bentham P, Gherghel D. Retinal vascular dysfunction relates to cognitive impairment in Alzheimer disease. Alzheimer Disease and Associated Disorders. 2014; 28: 366–367.
[196] Ning A, Cui J, To E, Ashe KH, Matsubara J. Amyloid‐β deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Investigative Ophthalmology & Visual Science. 2008; 49: 5136–5143.
[197] Liu B, Rasool S, Yang Z, Glabe CG, Schreiber SS, Ge J, et al. Amyloid‐peptide vaccinations reduce β‐amyloid plaques but exacerbate vascular deposition and inflammation in the retina of Alzheimer’s transgenic mice. American Journal of Pathology. 2009; 175: 2099–2110.
[198] Gasparini L, Anthony Crowther R, Martin KR, Berg N, Coleman M, Goedert M, et al. Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiology of Aging. 2011; 32: 419–433.
[199] 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: S204– S217.
[200] Kayabasi U, Sergott R, Rispoli M. Retinal examination for the diagnosis of Alzheimer’s disease. International Journal of Ophthalmic Pathology. 2014; 3: 4.
[201] Campbell MC, DeVries D, Emptage L, Cookson C, Kisilak M, Bueno J, Avila F. Polarization properties of amyloid beta in the retina of the eye as a biomarker of Alzheimer’s disease. In Optics in the life sciences, OSA technical digest (online). Optical Society of America; 2015, paper BM3A.4.
[202] Gharbiya M, Trebbastoni A, Parisi F, Manganiello S, Cruciani F, D’Antonio F, et al. Choroidal thinning as a new finding in Alzheimer’s disease: evidence from enhanced depth imaging spectral domain optical coherence tomography. Journal of Alzheimer’s Disease. 2014; 40: 907–917.
[203] Bayhan HA, Aslan Bayhan S, Celikbilek A, Tanık N, Gürdal C. Evaluation of the chorioretinal thickness changes in Alzheimer’s disease using spectral-domain optical coherence tomography. Clinical & Experimental Ophthalmology. 2014; 43: 145–151.
[204] Kam JH, Lenassi E, Jeffery G. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up‐regulation of macrophages. PLoS One. 2010; 5: e13127.
[205] Bailey TL, Rivara CB, Rocher AB, Hof PR. The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurological Research. 2004; 26: 573–578.
[206] Marchesi VT. Alzheimer’s dementia begins as a disease of small blood vessels, damaged by oxidative‐induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB. 2011; 25: 5–13.
[207] Miao J, Xu F, Davis J, Otte‐Höller I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid β protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid β precursor protein. American Journal of Pathology. 2005; 167: 505–515.
[208] Syed AB, Armstrong RA, Smith C. A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer’s disease. Folia Neuropatholica. 2005; 43: 1–6.
[209] Kusbeci T, Kusbeci OY, Mas NG, Karabekir HS, Yavas G, Yucel A. Stereological evaluation of the optic nerve volume in Alzheimer disease. Journal of Craniofacial Surgery. 2015; 26: 1683–1686.
[210] Cuzzo LM, Ross‐Cisneros FN, Yee KM, Wang MY, Sadun AA. Low density lipoprotein receptor‐related protein (LRP) is decreased in optic neuropathy of Alzheimer’s disease. Journal of Neuro‐ophthalmology. 2011; 31: 139–146.
[211] Wang MY, Ross‐Cisneros FN, Aggarwal D, Liang C, Sadun AA. Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer’s disease. Acta Neuropathologica. 2009; 118: 381–389.
[212] Tsai CS, Ritch R, Schwartz B, Lee SS, Miller NR, Chi T, et al. Optic nerve head and nerve fiber layer in Alzheimer’s disease. Archives of Ophthalmology. 1991; 109: 199–204.
[213] Kromer R, Serbecic N, Hausner L, Aboul‐enein F, Froelich L, Beutelspacher S. Detection of retinal nerve fiber layer defects in Alzheimer’s disease using SD‐OCT. Frontiers in Psychiatry. 2014; 5: 22.
[214] Danesh‐Meyer H, Birch H, Ku JYF, Carroll S, Gamble G. Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging. Neurology. 2006; 67: 1852–1854.
[215] Scholtz C, Swettenham K, Brown A, Mann D. A histoquantitative study of the striate cortex and lateral geniculate body in normal, blind and demented subjects. Neuropathology and Applied Neurobiology. 1981; 7: 103–114.
[216] Dugger BN, Tu M, Murray ME, Dickson DW. Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer’s disease and progressive supranuclear palsy. Neuroscience Letters. 2011; 491: 122–126.
[217] Iseki E, Matsushita M, Kosaka K, Kondo H, Ishii T, Amano N. Distribution and morphology of brain stem plaques in Alzheimer’s disease. Acta Neuropathologica. 1989; 78: 131–136.
[218] Leuba G, Saini K. Pathology of subcortical visual centres in relation to cortical degeneration in Alzheimer’s disease. Neuropathology and Applied Neurobiology. 1995; 21: 410–422.
[219] Parvizi J, Van Hoesen GW, Damasio A. The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Annals of Neurology. 2001; 49: 53–66.
[220] Katz B, Rimmer S. Ophthalmologic manifestations of Alzheimer’s disease. Survey of Ophthalmology. 1989; 34: 31–43.
[221] Dai J, Vliet JVD, Swaab DF, Buijs RM. Human retinohypothalamic tract as revealed by in vitro postmortem tracing. Journal of Comparative Neurology. 1998; 397: 357–370.
[222] Swaab DF, Fliers E, Partiman T. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Research. 1985; 342: 37–44.
[223] Goudsmit E, Hofman M, Fliers E, Swaab F. The supraoptic and paraventricular nuclei of the human hypothalamus in relation to sex, age and Alzheimer’s disease. Neurobiology of Aging. 1990; 11: 529–536.
[224] Stopa EG, Volicer L, Kuo‐Leblanc V, Harper D, Lathi D, Tate B, et al. Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. Journal of Neuropathology & Experimental Neurology. 1999; 58: 29–39.
[225] Harper DG, Stopa EG, Kuo‐Leblanc V, McKee AC, Asayama K, Volicer L, et al. Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia. Brain. 2008; 131: 1609–1617.
[226] Wu Y, Swaab DF. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Medicine. 2007; 8: 623–636.
[227] Kaas JH, Lyon DC. Pulvinar contributions to the dorsal and ventral streams of visual processing in primates. Brain Research Reviews. 2007; 55: 285–296.
[228] Kuljis RO. Lesions in the pulvinar in patients with Alzheimer’s disease. Journal of Neuropathology & Experimental Neurology. 1994; 53: 202–211.
[229] Braak H, Braak E. Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathologica. 1991; 82: 239–259.
[230] Braak H, Braak E. Evolution of neuronal changes in the course of Alzheimer’s disease. In: Jellinger K, Fazekas F, Windisch M, editors. Ageing and Dementia. Vienna: Springer; 1998. p. 127–140.
[231] Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, et al. The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid‐positive individuals. Cerebral Cortex. 2009; 19: 497–510.
[232] Hof PR, Bouras C, Constandinidis J, Morrison JH. Balit’s syndrome in Alzheimer’s disease: specific disruption of the occipito‐parietal visual pathway. Brain Research. 1989; 493: 368–375.
[233] Hof PR, Morrison JH. Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease. II. Primary and secondary visual cortex. Journal of Comparative Neurology. 1990; 301: 55–64.
[234] Buee L, Hof P, Bouras C, Delacourte A, Perl D, Morrison J, et al. Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders. Acta Neuropathologica. 1994; 87: 469–480.
[235] Wong‐Riley M, Antuono P, Ho K, Egan R, Hevner R, Liebl W, et al. Cytochrome oxidase in Alzheimer’s disease: biochemical, histochemical, and immunohistochemical analyses of the visual and other systems. Vision Research. 1997; 37: 3593–3608.
[236] Leuba G, Saini K. Pathology of subcortical visual centres in relation to cortical degemeration in Alzheimer’s disease. Neuropathology and Applied Neurobiology. 1995; 21: 410–422.
[237] Leuba G, Kraftsik R. Visual cortex in Alzheimer’s disease: Occurrence of neuronal death and glial proliferation, and correlation with pathological hallmarks. Neurobiology of Aging. 1994; 15: 29–43.
[238] Cronin‐Golomb A, Corkin S, Growdon JH. Visual dysfunction predicts cognitive deficits in Alzheimer’s disease. Optometry & Vision Science. 1995; 72: 168–176.
[239] Levine DN, Lee JM, Fisher C. The visual variant of Alzheimer’s disease A clinicopathologic case study. Neurology. 1993; 43: 305.
[240] Cohen J, Cronin‐Golomb A, Growdon JH, Corkin S. Color vision deficits in Alzheimer’s disease. Society for Neuroscience Abstracts. 1988; 14: 219.
[241] Martinelli V, Locatelli T, Comi G, Lia C, Alberoni M, Bressi S, et al. Pattern visual evoked potential mapping in Alzheimer’s disease correlations with visuospatial impairment. Dementia and Geriatric Cognitive disorders. 1996; 7: 63–68.
[242] Baloyannis S. Dendritic pathology in Alzheimer’s disease. Journal of the Neurological Sciences. 2009; 283: 153–157.
[243] Mavroudis IA, Fotiou DF, Manani MG, Njaou SN, Frangou D, Costa VG, et al. Dendritic pathology and spinal loss in the visual cortex in Alzheimer’s disease: a Golgi study in pathology. International Journal of Neuroscience. 2011; 121: 347–354.
[244] Cronin‐Golomb A, Corkin S, Rizzo JF, Cohen J, Growdon JH, Banks KS. Visual dysfunction in Alzheimer’s disease: relation to normal aging. Annals of Neurology. 1991; 29: 41–52.
[245] Mendez MF, Tomsak RL, Remler B. Disorders of the visual system in Alzheimer’s disease. Journal of Neuro‐Ophthalmology. 1990; 10: 62–69.
[246] Rizzo M, Nawrot M. Perception of movement and shape in Alzheimer’s disease. Brain. 1998; 121: 2259–2270.
[247] Sadun A, Borchert M, DeVita E, Hinton D, Bassi C. Assessment of visual impairment in patients with Alzheimer’s disease. American Journal of Ophthalmology. 1987; 104: 113–120.
[248] Murgatroyd C, Prettyman R. An investigation of visual hallucinosis and visual sensory status in dementia. International Journal of Geriatric Psychiatry. 2001; 16: 709–713.
[249] Chapman FM, Dickinson J, McKeith I, Ballard C. Association among visual hallucinations, visual acuity, and specific eye pathologies in Alzheimer’s disease: treatment implications. American Journal of Psychiatry. 1999; 156: 1983–1985.
[250] Uhlmann RF, Larson EB, Koepsell TD, Rees TS, Duckert LG. Visual impairment and cognitive dysfunction in Alzheimer’s disease. Journal of General Internal Medicine. 1991; 6: 126–132.
[251] Bassi CJ, Solomon K, Young D. Vision in aging and dementia. Optometry & Vision Science. 1993; 70: 809–813.
[252] Wood S, Mortel KF, Hiscock M, Breitmeyer BG, Caroselli JS. Adaptive and maladaptive utilization of color cues by patients with mild to moderate Alzheimer’s disease. Archives of Clinical Neuropsychology. 1997; 12: 483–489.
[253] Massoud F, Chertkow H, Whitehead V, Overbury O, Bergman H. Word‐reading thresholds in Alzheimer disease and mild memory loss: a pilot study. Alzheimer Disease & Associated Disorders. 2002; 16: 31–39.
[254] Rizzo III JF, Cronin‐Golomb A, Growdon JH, Corkin S, Rosen TJ, Sandberg MA, et al. Retinocalcarine function in Alzheimer’s disease: a clinical and electrophysiological study. Archives of Neurology. 1992; 49: 93–101.
[255] Shuren J, Heilman KM. Visual field loss in Alzheimer’s disease. Journal of the American Geriatrics Society. 1993; 41: 1114–1115.
[256] Whittaker K, Burdon M, Shah P. Visual field loss and Alzheimer’s disease. Eye. 2002; 16: 206–208.
[257] Gilmore GC, Levy JA. Spatial contrast sensitivity in Alzheimer’s disease: a comparison of two methods. Optometry & Vision Science. 1991; 68: 790–794.
[258] Gilmore GC, Whitehouse PJ. Contrast sensitivity in Alzheimer’s disease: a 1‐year longitudinal analysis. Optometry & Vision Science. 1995; 72: 83–91.
[259] Crow RW, Levin LB, LaBree L, Rubin R, Feldon SE. Sweep visual evoked potential evaluation of contrast sensitivity in Alzheimer’s dementia. Investigative Ophthalmology & Visual science. 2003; 44: 875–878.
[260] Hutton JT, Morris JL, Elias JW, Poston JN. Contrast sensitivity dysfunction in Alzheimer’s disease. Neurology. 1993; 43: 2328–2328.
[261] Baker D, Mendez M, Townsend J, Ilsen P, Bright D. Optometric management of patients with Alzheimer’s disease. Journal of the American Optometric Association. 1997; 68: 483–494.
[262] Cronin‐Golomb A, Gilmore GC, Neargarder S, Morrison SR, Laudate TM. Enhanced stimulus strength improves visual cognition in aging and Alzheimer’s disease. Cortex. 2007; 43: 952–966.
[263] Rami L, Serradell M, Bosch B, Villar A, Molinuevo JL. Perception Digital Test (PDT) for the assessment of incipient visual disorder in initial Alzheimer’s disease. Neurologia. 2007; 22: 342–347.
[264] Curran S, Wilson S, Musa S, Wattis J. Critical Flicker Fusion Threshold in patients with Alzheimer’s disease and vascular dementia. International Journal of Geriatric Psychiatry. 2004; 19: 575–581.
[265] Valdés M, De Flores T. Psychobiology of stress. Barcelona: Martínez Roca; 1985.
[266] Carmel D, Lavie N, Rees G. Conscious awareness of flicker in humans involves frontal and parietal cortex. Current Biology. 2006; 16: 907–911.
[267] Mendola JD, Cronin‐Golomb A, Corkin S, Growdon JH. Prevalence of visual deficits in Alzheimer’s disease. Optometry and Vision Science. 1995; 72: 155–167.
[268] Curran S, Wattis J. Critical flicker fusion threshold: a potentially useful measure for the early detection of Alzheimer’s disease. Human Psychopharmacology: Clinical and Experimental. 2000; 15: 103–112.
[269] Jackson GR, Owsley C, McGwin G. Aging and dark adaptation. Vision Research. 1999; 39: 3975–3982.
[270] Blake R, Wilson H. Binocular vision. Vision Research. 2011; 51: 754–770.
[271] Kiyosawa M, Bosley T, Chawluk J, Jamieson D, Schatz N, Savino P, et al. Alzheimer’s disease with prominent visual symptoms. Clinical and metabolic evaluation. Ophthalmology. 1989; 96: 1077–1085; discussion 1085–1086.
[272] Mendez M, Chekrier M, Meadows R. Depth perception in Alzheimer’s disease. Perceptual and Motor Skills. 1996; 83: 987–995.
[273] Thiyagesh SN, Farrow TF, Parks RW, Accosta‐Mesa H, Young C, Wilkinson ID, et al. The neural basis of visuospatial perception in Alzheimer’s disease and healthy elderly comparison subjects: an fMRI study. Psychiatry Research: Neuroimaging. 2009; 172: 109–116.
[274] Vaney DI, Sivyer B, Taylor WR. Direction selectivity in the retina: symmetry and asymmetry in structure and function. Nature Reviews Neuroscience. 2012; 13: 194–208.
[275] Chapman C, Hoag R, Giaschi D. The effect of disrupting the human magnocellular pathway on global motion perception. Vision Research. 2004; 44: 2551–2557.
[276] Skottun B. On the use of visual motion perception to assess magnocellular integrity. Journal of Integrative Neuroscience. 2011; 10: 15–32.
[277] Trick GL, Silverman SE. Visual sensitivity to motion age-related changes and deficits in senile dementia of the Alzheimer type. Neurology. 1991; 41: 1437–1437.
[278] Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry. 1999; 66: 137–147.
[279] Tales A, Troscianko T, Lush D, Haworth J, Wilcock G, Butler S. The pupillary light reflex in aging and Alzheimer’s disease. Aging. 2001; 13: 473–478.
[280] Fotiou F, Fountoulakis K, Tsolaki M, Goulas A, Palikaras A. Changes in pupil reaction to light in Alzheimer’s disease patients: a preliminary report. International Journal of Psychophysiology. 2000; 37: 111–120.
[281] Prettyman R, Bitsios P, Szabadi E. Altered pupillary size and darkness and light reflexes in Alzheimer’s disease. Journal of Neurology, Neurosurgery & Psychiatry. 1997; 62: 665–668.
[282] Scinto LF, Daffner KR, Dressler D, Ransil BI, Rentz D, Weintraub S, et al. A potential noninvasive neurobiological test for Alzheimer’s disease. Science. 1994; 266: 1051–1054.
[283] Ferrario E, Molaschi M, Villa L, Varetto O, Bogetto C, Nuzzi R. Is videopupillography useful in the diagnosis of Alzheimer’s disease? Neurology. 1998; 50: 642–644.
[284] FitzSimon JS, Waring SC, Kokmen E, McLaren JW, Brubaker RF. Response of the pupil to tropicamide is not a reliable test for Alzheimer disease. Archives of Neurology. 1997; 54: 155–159.
[285] Fridh M, Havelius U, Elofsson G, Hindfelt B. The pupillary response to tropicamide in Alzheimer’s disease. Acta Ophthalmologica Scandinavica. 1996; 74: 276–279.
[286] Graff‐Radford NR, Lin SC, Brazis PW, Bolling JP, Liesegang TJ, Lucas JA, Uitti RJ, O’Brien PC. Tropicamide eyedrops cannot be used for reliable diagnosis of Alzheimer’s disease. Mayo Clinic Proceedings. 1997; 72: 495–504.
[287] Growdon JH, Graefe K, Tennis M, Hayden D, Schoenfeld D, Wray SH. Pupil dilation to tropicamide is not specific for Alzheimer disease. Archives of Neurology. 1997; 54: 841–844.
[288] Kálmán J, Kanka A, Maglóczky E, Szóke A, Járdánházy T, Janka Z. Increased mydriatic response to tropicamide is a sign of cholinergic hypersensitivity but not specific to late-onset sporadic type of Alzheimer’s dementia. Biological Psychiatry. 1997; 41: 909–911.
[289] Kurz A, Marquard R, Fremke S, Leipert K. Pupil dilation response to tropicamide: a biological test for Alzheimer’s disease? Pharmacopsychiatry. 1997; 30: 12–15.
[290] Loupe DN, Newman NJ, Green RC, Lynn MJ, Williams KK, Geis TC, et al. Pupillary response to tropicamide in patients with Alzheimer disease. Ophthalmology. 1996; 103: 495–503.
[291] Treloar A, Assin M, MacDonald A. Pupillary response to topical tropicamide as a marker for Alzheimer’s disease. British Journal of Clinical Pharmacology. 1996; 41: 256–257.
[292] Gómez-Tortosa E, Barrio A, Jiménez-Alfaro I. Pupil response to tropicamide in Alzheimer’s disease and other neurodegenerative disorders. Acta Neurologica Scandinavica. 1996; 94: 104–109.
[293] Granholm E, Morris S, Galasko D, Shults C, Rogers E, Vukov B. Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer’s and Parkinson’s disease. International Journal of Psychophysiology. 2003; 47: 95–115.
[294] Grünberger J, Linzmayer L, Walter H, Rainer M, Masching A, Pezawas L, et al. Receptor test (pupillary dilatation after application of 0.01% tropicamide solution) and determination of central nervous activation (Fourier analysis of pupillary oscillations) in patients with Alzheimer’s disease. Neuropsychobiology. 1999; 40: 40–46.
[295] Hou R, Samuels E, Raisi M, Langley R, Szabadi E, Bradshaw C. Why patients with Alzheimer’s disease may show increased sensitivity to tropicamide eye drops: role of locus coeruleus. Psychopharmacology. 2006; 184: 95–106.
[296] Iijima A, Haida M, Ishikawa N, Ueno A, Minamitani H, Shinohara Y. Re‐evaluation of tropicamide in the pupillary response test for Alzheimer’s disease. Neurobiology of Aging. 2003; 24: 789–796.
[297] Kaneyuki H, Mitsuno S, Nishida T, Yamada M. Enhanced miotic response to topical dilute pilocarpine in patients with Alzheimer’s disease. Neurology. 1998; 50: 802–804.
[298] Reitner A, Baumgartner I, Thuile C, Dilmaghani R, Ergun E, Kaminsky S, et al. The mydriatic effect of tropicamide and its diagnostic use in Alzheimer’s disease. Vision Research. 1997; 37: 165–168.
[299] Levin LA, Nilsson SFE, Ver Hoeve J, Wu S, Kaufman PL, Alm A. Adler’s physiology of the eye. Elsevier Health Sciences; 2011. p. 796.
[300] Rüb U, Del Tredici K, Schultz C, Büttner‐Ennever J, Braak H. The premotor region essential for rapid vertical eye movements shows early involvement in Alzheimer’s disease‐related cytoskeletal pathology. Vision research. 2001; 41: 2149–2156.
[301] Boxer AL, Garbutt S, Seeley WW, Jafari A, Heuer HW, Mirsky J, et al. Saccade abnormalities in autopsy‐confirmed frontotemporal lobar degeneration and Alzheimer disease. Archives of Neurology. 2012; 69: 509.
[302] McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, et al. ISCEV Standard for full‐field clinical electroretinography (2015 update). Documenta Ophthalmologica. 2015; 130: 1–12.
[303] Strenn K, Dal‐Bianco P, Weghaupt H, Koch G, Vass C, Gottlob I. Pattern electroretinogram and luminance electroretinogram in Alzheimer’s disease. Journal of Neural Transmission Suppl. 1991; 33: 73–80.
[304] Prager TC, Schweitzer FC, Peacock LW, Garcia CA. The effect of optical defocus on the pattern electroretinogram in normal subjects and patients with Alzheimer’s disease. American Journal of Ophthalmology. 1993; 116: 363–369.
[305] Nesher R, Trick GL. The pattern electroretinogram in retinal and optic nerve disease. Documenta Ophthalmologica. 1991; 77: 225–235.
[306] Sartucci F, Borghetti D, Bocci T, Murri L, Orsini P, Porciatti V, et al. Dysfunction of the magnocellular stream in Alzheimer’s disease evaluated by pattern electroretinograms and visual evoked potentials. Brain Research Bulletin. 2010; 82: 169–176.
[307] M Moschos M, Markopoulos I, Chatziralli I, Rouvas A, G Papageorgiou S, Ladas I, et al. Structural and functional impairment of the retina and optic nerve in Alzheimer’s disease. Current Alzheimer Research. 2012; 9: 782–788.
[308] Simao LM. The contribution of optical coherence tomography in neurodegenerative diseases. Current Opinion in Ophthalmology. 2013; 24: 521–527.
[309] He XF, Liu YT, Peng C, Zhang F, Zhuang S, Zhang JS. Optical coherence tomography assessed retinal nerve fiber layer thickness in patients with Alzheimer’s disease: a meta-analysis. International Journal of Ophthalmology. 2012; 5: 401–405.
[310] Lu Y, Li Z, Zhang X, Ming B, Jia J, Wang R, et al. Retinal nerve fiber layer structure abnormalities in early Alzheimer’s disease: evidence in optical coherence tomography. Neuroscience Letters. 2010; 480: 69–72.
[311] Chi Y, Wang YH, Yang L. The investigation of retinal nerve fiber loss in Alzheimer’s disease. Chinese Journal of Ophthalmology. 2010; 46: 134–139.
[312] Shen Y, Shi Z, Jia R, Zhu Y, Cheng Y, Feng W, et al. The attenuation of retinal nerve fiber layer thickness and cognitive deterioration. Frontiers in Cellular Neuroscience. 27 2013; 7: 142.
[313] Kirbas S, Turkyilmaz K, Anlar O, Tufekci A, Durmus M. Retinal nerve fiber layer thickness in patients with Alzheimer disease. Journal of Neuro‐Ophthalmology. 2013; 33: 58–61.
[314] Oktem EO, Derle E, Kibaroglu S, Oktem C, Akkoyun I, Can U. The relationship between the degree of cognitive impairment and retinal nerve fiber layer thickness. Neurological Sciences. 2015; 36: 1141–1146.
[315] Ascaso FJ, Cruz N, Modrego PJ, Lopez‐Anton R, Santabárbara J, Pascual LF, et al. Retinal alterations in mild cognitive impairment and Alzheimer’s disease: an optical coherence tomography study. Journal of Neurology. 2014; 261: 1522–1530.
[316] Liu D, Zhang L, Li Z, Zhang X, Wu Y, Yang H, et al. Thinner changes of the retinal never fiber layer in patients with mild cognitive impairment and Alzheimer’s disease. BMC Neurology. 2015; 15: 14.
[317] Cheung CY, Ong YT, Hilal S, Ikram MK, Low S, Ong YL, et al. Retinal ganglion cell analysis using high‐definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer’s disease. Journal of Alzheimer’s Disease. 2015; 45: 45–56.
[318] Vickers J. The cellular mechanism underlying neuronal degeneration in glaucoma: parallels with Alzheimer’s disease. Australian and New Zealand Journal of Ophthalmology. 1997; 25: 105–109.
[319] McKinnon SJ. Glaucoma: ocular Alzheimer’s disease. Frontiers in Bioscience. 2003; 8: s1140–s1156.
[320] Guo L, Duggan J, Cordeiro M. Alzheimers disease and retinal neurodegeneration. Current Alzheimer Research. 2010; 7: 3–14.
[321] Bayer A, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer’s disease. European Neurology. 2002; 47: 165–168.
[322] Tamura H, Kawakami H, Kanamoto T, Kato T, Yokoyama T, Sasaki K, et al. High frequency of open‐angle glaucoma in Japanese patients with Alzheimer’s disease. Journal of the Neurological Sciences. 2006; 246: 79–83.
[323] Lipton SA. Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Survey of Ophthalmology. 2003; 48: S38–S46.
[324] Osborne NN. Recent clinical findings with memantine should not mean that the idea of neuroprotection in glaucoma is abandoned. Acta Ophthalmologica. 2009; 87: 450–454.
[325] Bach-Holm D, Kessing SV, Mogensen U, Forman JL, Andersen PK, Kessing LV. Normal tension glaucoma and Alzheimer disease: comorbidity? Acta Ophthalmologica. 2012; 90: 683–685.