Abstract
Context:
Visual disturbances are frequent in Alzheimer’s disease (AD) and sometimes AD begins with visual disturbances, therefore many researchers have examined the eyes in order to confirm the diagnosis, to monitor the development of the disease or the response to drugs.Evidence Acquisition:
Medline literature until March 2018.Results:
Several indications suggest an early involvement of the visual system in AD, yet this evidence remains inconclusive. The reason for this uncertainty is two folds: The poor quality of the studies and the fact that some alterations are not unique to the AD, since they also occur in others degenerative CNS diseases.Conclusions:
The eye can be a perfect place for early diagnosis of AD and to evaluate the effectiveness of therapies more studies are needed.Keywords
1. Context
Usually the Alzheimer’s disease (AD) is regarded as a cognitive disease. However, evidence shows typical lesions of AD in the brain as well as in the spinal cord or even outside the central nervous system (CNS). Non-cognitive symptoms, mostly motor or psychiatric, are also recurrent in AD (1). The retina is part of the CNS and is easy to study. On the other hand, visual disturbances are frequent in AD patients (2) and sometimes AD begins with visual symptoms (3). Therefore, many researchers have examined the eyes and mainly the retina in order to confirm the diagnosis, to monitor the development of the disease or the response to drugs. The aim of this work was to review the literature in regards to the involvment of the eye in AD. In the first part, this research examined the involvment of the visual system in animal models and in pathological studies in humans; in the second part, clinical studies were reviewed.
2. Evidence Acquisition
Medline literature until March 2018 was scanned using “ocular disease and AD” and “ocular biomarker and AD”, as keywords. When ocular disturbances were identified, the search was narrowed using “ocular saccades and AD”, “optic nerve and AD”, “retina and AD”, “glaucoma and AD”, “cataract and AD”, and “age-related maculopathy and AD”. Additional studies were identified by reviewing relevant bibliography quoted in the original papers. Clinical studies were incluted in this review whenever they could meet three fundamental criteria: (1) AD diagnosis according to NINCDS-ADRDA criteria (4); (2) studies including patients with dementias other than AD were considered when sufficient data on AD was provided; (3) use of standardized instruments of evaluation.
3. Results
Alziemer’s disease normally has an amnestic presentation, yet a non-amnestic presentation is also possible and in fact some claim that the memory function and the visuomotor function are equally impaired (5). The visual variant of the AD was described by Grunthal (6); in Snowden’s et al. series (7) the frequency was 5%. The authors did not notice any discrepancy with classical AD concerning gender distribution, age at onset, neurological signs, family history of dementia, and APOE. While the opening symptoms may be non-specific and the ophthalmic examination normal, some specific deficits might characterize certain cases. In their series, Lee and Martin (8) referred homonymous visual field loss in four out of eight patients and cortical visual impairment in two out of eight. In rare cases, the authors detected a complete Balint’s syndrome (simultanagnosia, oculomotor apraxia and optic ataxia) (6). The MRI showed atrophy in the parieto-occipital regions and the single-photon emission computed tomography (SPECT) and PET decreased metabolism or hypoperfusion in the same regions (3, 9). However, in the classical form, AD disturbances of the visual pathway were documented. The analysis of visual signals is processed through two pathways: the ventral pathway, the so-called “what pathway”, begins in the V1 area of the occipital cortex and reaches the temporal lobe. This pathway is involved in the perception and identification of objects and in long-term memory. The dorsal pathway, the so-called “where pathway”, begins in the V1 area of the occipital cortex and reaches the parietal lobe and is associated with visuospatial processing, spatial working memory, and visually-guided actions (10). Mentis et al. (11) showed decreased regional cerebral flow in the striate; the authors hypothesized a greater magnocellular dysfunction. Using functional MRI (fMRI) in MCI patients, Teipel et al. (12) found a positive correlation between the activation of the fusiform gyrus and the ventral temporal lobes and a negative correlation with the frontal lobes. By using fMRI, Vannini et al. (13) showed alterations of the visual pathway, suggesting a failure to modulate the neural response to increased task demand. Thulborn et al. (14) showed lesser parietal activation and greater prefrontal activation. These results were confirmed by Prvulovic et al. (15), along with greater activity of the fusiform gyrus; the authors hypothesize a mechanism to compensate for the reduced functional capacity of the superior parietal lobule. Using fMRI in MCI patients, Bokde et al. (16) showed no selective activation of the visual system’s pathway; instead, they found higher activation in the frontal lobes. On the other side, Alichniewicz et al. (17) found decreased activation in frontal eyes fields, and Jacobs et al. (18) found increased activation in the visual pathways of MCI and early AD patients. By using diffusion tension imaging, Nishioka et al. (19) demonstrated that the visual pathway from the eyes to the brain is affected both in the MCI and, to a greater extend, in the AD; pathological changes were found mainly in the optic nerves. In a heterogenous series of patients with tau pathology, Rahimi et al. (20) found tau deposition both in the optic nerve and in the lateral geniculate nucleus. The visual pathways were also examined using visual evoked potentials (VEP) with conflicting results. BY using pattern VEP, some Authors described prolonged latencies (21), whereas others found prolonged latencies only by flash VEP (22). Studies based on flash VEP also found differences between patients and control groups; however, for a single patient the difference was too small to contribute to the diagnosis (23). Reduced amplitude also positively correlated with the degree of the cognitive impairment (24). Relying on electroretinogram (ERG) and VEP, Sartucci et al. (25) suggest a primary disfunction of the magnocellular stream. Ponomareva et al. (26) found prolonged latencies among the relatives of the patients and Rosengarten et al. (27) claimed that patients with APOE4 have latencies significantly longer than patients without APOE4. Finally, Leinonen et al. (28) found normal VEP in the AβPP/PS1 mice while the ERG shortened in latency, thus, suggesting changes only in the retina.
Several authors examined visual deficits using neuropsychological tests and reaching discordant results. Indeed some recognized visuospatial deficits in the early stages (5, 29) whereas others found evidence only in the latter stages of the disease (30, 31). According to Paxton et al. (30), these deficits may be useful in tracking the disease’s course. Some authors identified a selective damage of the posterior pathway (32) whereas others claimed that AD affects multiple visual pathways and regions (29). The ocular motility is controlled by a complex network (33), which can easily be damaged by pathological processes and has therefore been extensively examined in AD research. Several authors reported increased latency to initiate saccades (34-36), while Shakespeare et al. (37) reported normal latency accompanied by unusual high square wave jerks during fixation and lower maximum period of fixation. Yang et al. (38) reported increased latency also in the MCI. Other studies reported pathological findings in some measures of the saccades, including a reduced peak velocity (39) or reduced gain (40). Garbutt et al. (41) reported reduced gain also in the supranuclear paralysis and in corticobasal degeneration. Anticipatory saccades were referred by Abel et al. (42) and Shafiq-Antonacci et al. (35). Other authors referred saccadic intrusions (34, 36) and Boxer et al. (36) claimed a correlation with the frontal tests. Other authors described altered anti-saccades (35, 36, 43-45); Boxer et al. (36) found the same alterations in the frontotemporal dementia, while Crawford et al. (43) referred normal anti-saccades in Parkinson’s disease. Some authors indicated a correlation between pathological anti-saccades and the degree of dementia (43, 44); Crawford et al. (46) suggested a correlation with the spatial working memory and Peltsch et al. (45) with the Stroop test. On the other hand, Kaufman et al. (47) found no correlation with dementia and Heuer et al. (44) found normal values in the MCI. While studying more complex movements, authors suggested more frequent or longer fixation (40), diminished visual exploration (48), and decreased attention to the incongrous part of a figure (49).
In 1994, Scinto et al. (50) described marked hypersensitivity in pupil dilatation response to Tropicamide, a cholinergic antagonist. This was confirmed by Grunberger et al. (51) yet not by others (52). Hypersensitivity was found only in the early-onset AD (53) or in other diseases (54). Pupillometry was used to identify a cholinergic deficiency and several alterations were found in the AD. Tales et al. (55) referred reduced amplitude of the pupillary constriction to light; Fotiou et al. (56) found an impaired pupillary light reflex, suggesting that an acceleration of the maximum constriction could be the best AD predictor. The same authors (56) found a correlation between maximum constriction velocity and maximum constriction acceleration with MMSE and Wechsler memory scale. Many authors examined the retina and with few exceptions (57), all agreed on reduced retinal fibre layer (RNFL) (58-60). A reduced RNFL was often found in the superior quadrant (58-60). However, similar observations were also made in other CNS diseases (61). Several authors have examined a possible association between glaucoma and AD. Tsilis et al.’s (62) meta-analysis was unsuccessful because the data were too heterogeneous to draw any conclusion. None of the following works brought to conclusive evidence: While some authors found a positive association (63) others claimed the opposite (64). Regarding glaucoma, several works showed morphological and functional changes in the visual and non-visual systems (65). The importance of these observations is currently debated; however, because these changes are also present in the early stages, their presence could be at least partially independent on raised intraocular pressure. Theoretically, several mechanisms can be common in these two diseases. Neurotoxicity has also been hypothesized: in vitreous samples, elevated tau and decreased amyloid levels were detected (66). Berdahl et al. (67) referred reduction of 3 to 4 mmHg in intracranial pressure in subjects with primary open angle glaucoma suggesting that the transluminal pressure gradient (the difference between intraocular and intracranial pressure) plays an important role in the genesis of the glaucoma. A meta-analysis (68) confirmed that higher transluminal pressure is related to structural glaucomatous changes. A link between age-related macular degeneration (AMD) and AD was also hypothesized given the many similarities between these two diseases as the presence of some molecular components i.e. β-amyloid and vitronectin, and complement activation (69). Several authors claimed a positive link (70), while others did not confirm this (71). In 2003, Goldstein et al. (72) referred a greater frequency of supra-nuclear cataract in AD; this finding was later confirmed in AD (73), Down syndrome (74) and transgenic animals (75). Some authors did not confirm this finding (76) while Lai et al. (77) found a greater frequency of cataract in Parkinson’s disease.
4. Conclusions
Considering embryonal development, it is clear that the eye represents an optimal site for an early diagnosis of AD and for evaluating the effectiveness of the therapies. Several indications suggest an early involvement of the visual system in AD, yet this evidence remains inconclusive. The reason for this uncertainty is two folds. The first reason is the poor quality of the studies: Often the series are too small and the severity of the disease varies too widely to make a rigorous comparison possible. The second reason is that some alterations are not unique to AD, since they also occur in others degenerative CNS diseases. For example, α-synuclein and tau-pathology in the visual system was found in patients with AD and Parkinson’s disease (20, 77). It is therefore possible to hypothesize that taupathies and some ocular diseases have common pathogenetic pathways. The identification of an AD-related ocular pathology might be a cheaper and easier diagnostic tool than the MRI or the lumbar puncture. However, this is also of theoretical importance because AD is usually regarded as a disease affecting cognitive status yet in the literature, several non-cognitive symptoms are described, such as motor, psychiatric or epileptic in the early stages or in the MCI (1). Recovering a metaphor used by Langston (78), it could be suggested that AD’s cognitive symptoms might in fact only represent the tip of the iceberg.
References
-
1.
Raudino F. Non-cognitive symptoms and related conditions in the Alzheimer's disease: A literature review. Neurol Sci. 2013;34(8):1275-82. [PubMed ID: 23543394]. https://doi.org/10.1007/s10072-013-1424-7.
-
2.
Bowen M, Edgar DF, Hancock B, Haque S, Shah R, Buchanan S, et al. The prevalence of visual impairment in people with dementia (the PrOVIDe study): A cross-sectional study of people aged 60-89 years with dementia and qualitative exploration of individual, carer and professional perspectives. Health Services and Delivery Research Southampton (UK): NIHR Journals Library; 2016. eng. https://doi.org/10.3310/hsdr04210.
-
3.
Kaeser PF, Ghika J, Borruat FX. Visual signs and symptoms in patients with the visual variant of Alzheimer disease. BMC Ophthalmol. 2015;15:65. [PubMed ID: 26122482]. [PubMed Central ID: PMC4485862]. https://doi.org/10.1186/s12886-015-0060-9.
-
4.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology. 1984;34(7):939-44. [PubMed ID: 6610841].
-
5.
de Boer C, Mattace-Raso F, van der Steen J, Pel JJ. Mini-mental state examination subscores indicate visuomotor deficits in Alzheimer's disease patients: A cross-sectional study in a Dutch population. Geriatr Gerontol Int. 2014;14(4):880-5. [PubMed ID: 24237759]. https://doi.org/10.1111/ggi.12183.
-
6.
Grunthal E. Zur hirnpathologischen analyse der alzheimerschen krankheit. Psychiatrisch neurologische wochenschrift. 36. Fb&c Limited; 1928. p. 401-7.
-
7.
Snowden JS, Stopford CL, Julien CL, Thompson JC, Davidson Y, Gibbons L, et al. Cognitive phenotypes in Alzheimer's disease and genetic risk. Cortex. 2007;43(7):835-45. [PubMed ID: 17941342].
-
8.
Lee AG, Martin CO. Neuro-ophthalmic findings in the visual variant of Alzheimer's disease. Ophthalmology. 2004;111(2):376-80. discussion 380-1. [PubMed ID: 15019393]. https://doi.org/10.1016/S0161-6420(03)00732-2.
-
9.
Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. The topography of metabolic deficits in posterior cortical atrophy (the visual variant of Alzheimer's disease) with FDG-PET. J Neurol Neurosurg Psychiatry. 2003;74(11):1521-9. [PubMed ID: 14617709]. [PubMed Central ID: PMC1738241].
-
10.
Khan ZU, Martin-Montanez E, Baxter MG. Visual perception and memory systems: From cortex to medial temporal lobe. Cell Mol Life Sci. 2011;68(10):1737-54. [PubMed ID: 21365279]. https://doi.org/10.1007/s00018-011-0641-6.
-
11.
Mentis MJ, Horwitz B, Grady CL, Alexander GE, VanMeter JW, Maisog JM, et al. Visual cortical dysfunction in Alzheimer's disease evaluated with a temporally graded "stress test" during PET. Am J Psychiatry. 1996;153(1):32-40. [PubMed ID: 8540589]. https://doi.org/10.1176/ajp.153.1.32.
-
12.
Teipel SJ, Bokde AL, Born C, Meindl T, Reiser M, Moller HJ, et al. Morphological substrate of face matching in healthy ageing and mild cognitive impairment: A combined MRI-fMRI study. Brain. 2007;130(Pt 7):1745-58. [PubMed ID: 17566054]. https://doi.org/10.1093/brain/awm117.
-
13.
Vannini P, Lehmann C, Dierks T, Jann K, Viitanen M, Wahlund LO, et al. Failure to modulate neural response to increased task demand in mild Alzheimer's disease: fMRI study of visuospatial processing. Neurobiol Dis. 2008;31(3):287-97. [PubMed ID: 18619845]. https://doi.org/10.1016/j.nbd.2008.04.013.
-
14.
Thulborn KR, Martin C, Voyvodic JT. Functional MR imaging using a visually guided saccade paradigm for comparing activation patterns in patients with probable Alzheimer's disease and in cognitively able elderly volunteers. AJNR Am J Neuroradiol. 2000;21(3):524-31. [PubMed ID: 10730646].
-
15.
Prvulovic D, Hubl D, Sack AT, Melillo L, Maurer K, Frolich L, et al. Functional imaging of visuospatial processing in Alzheimer's disease. Neuroimage. 2002;17(3):1403-14. [PubMed ID: 12414280].
-
16.
Bokde AL, Lopez-Bayo P, Born C, Dong W, Meindl T, Leinsinger G, et al. Functional abnormalities of the visual processing system in subjects with mild cognitive impairment: An fMRI study. Psychiatry Res. 2008;163(3):248-59. [PubMed ID: 18672352]. https://doi.org/10.1016/j.pscychresns.2007.08.013.
-
17.
Alichniewicz KK, Brunner F, Klunemann HH, Greenlee MW. Neural correlates of saccadic inhibition in healthy elderly and patients with amnestic mild cognitive impairment. Front Psychol. 2013;4:467. [PubMed ID: 23898312]. [PubMed Central ID: PMC3721022]. https://doi.org/10.3389/fpsyg.2013.00467.
-
18.
Jacobs HI, Gronenschild EH, Evers EA, Ramakers IH, Hofman PA, Backes WH, et al. Visuospatial processing in early Alzheimer's disease: A multimodal neuroimaging study. Cortex. 2015;64:394-406. [PubMed ID: 22342463]. https://doi.org/10.1016/j.cortex.2012.01.005.
-
19.
Nishioka C, Poh C, Sun SW. Diffusion tensor imaging reveals visual pathway damage in patients with mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2015;45(1):97-107. [PubMed ID: 25537012]. [PubMed Central ID: PMC4500052]. https://doi.org/10.3233/JAD-141239.
-
20.
Rahimi J, Milenkovic I, Kovacs GG. Patterns of Tau and alpha-synuclein pathology in the visual system. J Parkinsons Dis. 2015;5(2):333-40. [PubMed ID: 25737267]. https://doi.org/10.3233/JPD-140485.
-
21.
Krasodomska K, Lubinski W, Potemkowski A, Honczarenko K. Pattern electroretinogram (PERG) and pattern visual evoked potential (PVEP) in the early stages of Alzheimer's disease. Doc Ophthalmol. 2010;121(2):111-21. [PubMed ID: 20549299]. [PubMed Central ID: PMC2941083]. https://doi.org/10.1007/s10633-010-9238-x.
-
22.
Philpot MP, Amin D, Levy R. Visual evoked potentials in Alzheimer's disease: Correlations with age and severity. Electroencephalogr Clin Neurophysiol. 1990;77(5):323-9. [PubMed ID: 1697523].
-
23.
Coburn KL, Arruda JE, Estes KM, Amoss RT. Diagnostic utility of visual evoked potential changes in Alzheimer's disease. J Neuropsychiatry Clin Neurosci. 2003;15(2):175-9. [PubMed ID: 12724458]. https://doi.org/10.1176/jnp.15.2.175.
-
24.
Stothart G, Kazanina N, Naatanen R, Haworth J, Tales A. Early visual evoked potentials and mismatch negativity in Alzheimer's disease and mild cognitive impairment. J Alzheimers Dis. 2015;44(2):397-408. [PubMed ID: 25261446]. https://doi.org/10.3233/JAD-140930.
-
25.
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 Res Bull. 2010;82(3-4):169-76. [PubMed ID: 20385208]. [PubMed Central ID: PMC3227554]. https://doi.org/10.1016/j.brainresbull.2010.04.001.
-
26.
Ponomareva NV, Fokin VF, Selesneva ND, Voskresenskaia NI. Possible neurophysiological markers of genetic predisposition to Alzheimer's disease. Dement Geriatr Cogn Disord. 1998;9(5):267-73. [PubMed ID: 9701678]. https://doi.org/10.1159/000017071.
-
27.
Rosengarten B, Paulsen S, Burr O, Kaps M. Effect of ApoE epsilon4 allele on visual evoked potentials and resultant flow coupling in patients with Alzheimer. J Geriatr Psychiatry Neurol. 2010;23(3):165-70. [PubMed ID: 20430978]. https://doi.org/10.1177/0891988710363711.
-
28.
Leinonen H, Lipponen A, Gurevicius K, Tanila H. Normal amplitude of electroretinography and visual evoked potential responses in abetaPP/PS1 mice. J Alzheimers Dis. 2016;51(1):21-6. [PubMed ID: 26836173]. https://doi.org/10.3233/JAD-150798.
-
29.
Velarde C, Perelstein E, Ressmann W, Duffy CJ. Independent deficits of visual word and motion processing in aging and early Alzheimer's disease. J Alzheimers Dis. 2012;31(3):613-21. [PubMed ID: 22647256]. [PubMed Central ID: PMC3732794]. https://doi.org/10.3233/JAD-2012-112201.
-
30.
Paxton JL, Peavy GM, Jenkins C, Rice VA, Heindel WC, Salmon DP. Deterioration of visual-perceptual organization ability in Alzheimer's disease. Cortex. 2007;43(7):967-75. [PubMed ID: 17941353].
-
31.
Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR. Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2001;70(2):157-64. [PubMed ID: 11160462]. [PubMed Central ID: PMC1737215].
-
32.
Stehli Nguyen A, Chubb C, Jacob Huff F. Visual identification and spatial location in Alzheimer's disease. Brain Cogn. 2003;52(2):155-66. [PubMed ID: 12821097].
-
33.
Girard B, Berthoz A. From brainstem to cortex: computational models of saccade generation circuitry. Prog Neurobiol. 2005;77(4):215-51. [PubMed ID: 16343730]. https://doi.org/10.1016/j.pneurobio.2005.11.001.
-
34.
Fletcher WA, Sharpe JA. Saccadic eye movement dysfunction in Alzheimer's disease. Ann Neurol. 1986;20(4):464-71. [PubMed ID: 3789662]. https://doi.org/10.1002/ana.410200405.
-
35.
Shafiq-Antonacci R, Maruff P, Masters C, Currie J. Spectrum of saccade system function in Alzheimer disease. Arch Neurol. 2003;60(9):1272-8. [PubMed ID: 12975294]. https://doi.org/10.1001/archneur.60.9.1272.
-
36.
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. Arch Neurol. 2012;69(4):509-17. [PubMed ID: 22491196]. [PubMed Central ID: PMC3423186]. https://doi.org/10.1001/archneurol.2011.1021.
-
37.
Shakespeare TJ, Kaski D, Yong KX, Paterson RW, Slattery CF, Ryan NS, et al. Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy. Brain. 2015;138(Pt 7):1976-91. [PubMed ID: 25895507]. [PubMed Central ID: PMC4572483]. https://doi.org/10.1093/brain/awv103.
-
38.
Yang Q, Wang T, Su N, Liu Y, Xiao S, Kapoula Z. Long latency and high variability in accuracy-speed of prosaccades in Alzheimer's disease at mild to moderate stage. Dement Geriatr Cogn Dis Extra. 2011;1(1):318-29. [PubMed ID: 22203824]. [PubMed Central ID: PMC3246280]. https://doi.org/10.1159/000333080.
-
39.
Fletcher WA, Sharpe JA. Smooth pursuit dysfunction in Alzheimer's disease. Neurology. 1988;38(2):272-7. [PubMed ID: 3340292].
-
40.
Fernandez G, Mandolesi P, Rotstein NP, Colombo O, Agamennoni O, Politi LE. Eye movement alterations during reading in patients with early Alzheimer disease. Invest Ophthalmol Vis Sci. 2013;54(13):8345-52. [PubMed ID: 24282223]. https://doi.org/10.1167/iovs.13-12877.
-
41.
Garbutt S, Matlin A, Hellmuth J, Schenk AK, Johnson JK, Rosen H, et al. Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer's disease. Brain. 2008;131(Pt 5):1268-81. [PubMed ID: 18362099]. [PubMed Central ID: PMC2367697]. https://doi.org/10.1093/brain/awn047.
-
42.
Abel LA, Unverzagt F, Yee RD. Effects of stimulus predictability and interstimulus gap on saccades in Alzheimer's disease. Dement Geriatr Cogn Disord. 2002;13(4):235-43. [PubMed ID: 12006734]. https://doi.org/10.1159/000057702.
-
43.
Crawford TJ, Higham S, Renvoize T, Patel J, Dale M, Suriya A, et al. Inhibitory control of saccadic eye movements and cognitive impairment in Alzheimer's disease. Biol Psychiatry. 2005;57(9):1052-60. [PubMed ID: 15860346]. https://doi.org/10.1016/j.biopsych.2005.01.017.
-
44.
Heuer HW, Mirsky JB, Kong EL, Dickerson BC, Miller BL, Kramer JH, et al. Antisaccade task reflects cortical involvement in mild cognitive impairment. Neurology. 2013;81(14):1235-43. [PubMed ID: 23986300]. [PubMed Central ID: PMC3795604]. https://doi.org/10.1212/WNL.0b013e3182a6cbfe.
-
45.
Peltsch A, Hemraj A, Garcia A, Munoz DP. Saccade deficits in amnestic mild cognitive impairment resemble mild Alzheimer's disease. Eur J Neurosci. 2014;39(11):2000-13. [PubMed ID: 24890471]. https://doi.org/10.1111/ejn.12617.
-
46.
Crawford TJ, Higham S, Mayes J, Dale M, Shaunak S, Lekwuwa G. The role of working memory and attentional disengagement on inhibitory control: Effects of aging and Alzheimer's disease. Age (Dordr). 2013;35(5):1637-50. [PubMed ID: 22903189]. [PubMed Central ID: PMC3776119]. https://doi.org/10.1007/s11357-012-9466-y.
-
47.
Kaufman LD, Pratt J, Levine B, Black SE. Executive deficits detected in mild Alzheimer's disease using the antisaccade task. Brain Behav. 2012;2(1):15-21. [PubMed ID: 22574270]. [PubMed Central ID: PMC3343295]. https://doi.org/10.1002/brb3.28.
-
48.
Viskontas IV, Boxer AL, Fesenko J, Matlin A, Heuer HW, Mirsky J, et al. Visual search patterns in semantic dementia show paradoxical facilitation of binding processes. Neuropsychologia. 2011;49(3):468-78. [PubMed ID: 21215762]. [PubMed Central ID: PMC3046767]. https://doi.org/10.1016/j.neuropsychologia.2010.12.039.
-
49.
Daffner KR, Scinto LF, Weintraub S, Guinessey JE, Mesulam MM. Diminished curiosity in patients with probable Alzheimer's disease as measured by exploratory eye movements. Neurology. 1992;42(2):320-8. [PubMed ID: 1736159].
-
50.
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(5187):1051-4. [PubMed ID: 7973660].
-
51.
Grunberger 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(1):40-6. [PubMed ID: 10420100]. https://doi.org/10.1159/000026595.
-
52.
Loupe DN, Newman NJ, Green RC, Lynn MJ, W. Illiams KK, Geis TC, et al. Pupillary response to tropicamide in patients with Alzheimer disease. Ophthalmology. 1996;103(3):495-503. [PubMed ID: 8600428].
-
53.
Takagi A, Miyao M, Ishihara S, Sakakibara H, Kondo T, Toyoshima H, et al. Sensitive pupil response of early-onset Alzheimer's patients to a dilute mixture of cholinergic antagonist and alpha-Adrenergic stimulant. Environ Health Prev Med. 1999;4(1):49-53. [PubMed ID: 21432171]. [PubMed Central ID: PMC2723423]. https://doi.org/10.1007/BF02931250.
-
54.
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. Int J Psychophysiol. 2003;47(2):95-115. [PubMed ID: 12568941].
-
55.
Tales A, Troscianko T, Lush D, Haworth J, Wilcock GK, Butler SR. The pupillary light reflex in aging and Alzheimer's disease. Aging (Milano). 2001;13(6):473-8. [PubMed ID: 11845975].
-
56.
Fotiou DF, Brozou CG, Haidich AB, Tsiptsios D, Nakou M, Kabitsi A, et al. Pupil reaction to light in Alzheimer's disease: Evaluation of pupil size changes and mobility. Aging Clin Exp Res. 2007;19(5):364-71. [PubMed ID: 18007114].
-
57.
Lad EM, Mukherjee D, Stinnett SS, Cousins SW, Potter GG, Burke JR, et al. Evaluation of inner retinal layers as biomarkers in mild cognitive impairment to moderate Alzheimer's disease. PLoS One. 2018;13(2). e0192646. [PubMed ID: 29420642]. [PubMed Central ID: PMC5805310]. https://doi.org/10.1371/journal.pone.0192646.
-
58.
Liu D, Zhang L, Li Z, Zhang X, Wu Y, Yang H, et al. Thinner changes of the retinal nerve fiber layer in patients with mild cognitive impairment and Alzheimer's disease. BMC Neurol. 2015;15:14. [PubMed ID: 25886372]. [PubMed Central ID: PMC4342899]. https://doi.org/10.1186/s12883-015-0268-6.
-
59.
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. Arch Gerontol Geriatr. 2015;60(1):162-7. [PubMed ID: 25459918]. https://doi.org/10.1016/j.archger.2014.10.011.
-
60.
Kwon JY, Yang JH, Han JS, Kim DG. Analysis of the retinal nerve fiber layer thickness in alzheimer disease and mild cognitive impairment. Korean J Ophthalmol. 2017;31(6):548-56. [PubMed ID: 29022297]. [PubMed Central ID: PMC5726990]. https://doi.org/10.3341/kjo.2016.0118.
-
61.
Jindahra P, Hedges TR, Mendoza-Santiesteban CE, Plant GT. Optical coherence tomography of the retina: Applications in neurology. Curr Opin Neurol. 2010;23(1):16-23. [PubMed ID: 20009925]. https://doi.org/10.1097/WCO.0b013e328334e99b.
-
62.
Tsilis AG, Tsilidis KK, Pelidou SH, Kitsos G. Systematic review of the association between Alzheimer's disease and chronic glaucoma. Clin Ophthalmol. 2014;8:2095-104. [PubMed ID: 25342880]. [PubMed Central ID: PMC4206373]. https://doi.org/10.2147/OPTH.S69534.
-
63.
Cesareo M, Martucci A, Ciuffoletti E, Mancino R, Cerulli A, Sorge RP, et al. Association between Alzheimer's disease and glaucoma: A study based on heidelberg retinal tomography and frequency doubling technology perimetry. Front Neurosci. 2015;9:479. [PubMed ID: 26733792]. [PubMed Central ID: PMC4683203]. https://doi.org/10.3389/fnins.2015.00479.
-
64.
Williams EA, McGuone D, Frosch MP, Hyman BT, Laver N, Stemmer-Rachamimov A. Absence of Alzheimer disease neuropathologic changes in eyes of subjects with Alzheimer disease. J Neuropathol Exp Neurol. 2017;76(5):376-83. [PubMed ID: 28379416]. https://doi.org/10.1093/jnen/nlx020.
-
65.
Giorgio A, Zhang J, Costantino F, De Stefano N, Frezzotti P. Diffuse brain damage in normal tension glaucoma. Hum Brain Mapp. 2018;39(1):532-41. [PubMed ID: 29064608]. https://doi.org/10.1002/hbm.23862.
-
66.
Yoneda S, Hara H, Hirata A, Fukushima M, Inomata Y, Tanihara H. Vitreous fluid levels of beta-amyloid((1-42)) and tau in patients with retinal diseases. Jpn J Ophthalmol. 2005;49(2):106-8. [PubMed ID: 15838725]. https://doi.org/10.1007/s10384-004-0156-x.
-
67.
Berdahl JP, Fautsch MP, Stinnett SS, Allingham RR. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: A case-control study. Invest Ophthalmol Vis Sci. 2008;49(12):5412-8. [PubMed ID: 18719086]. [PubMed Central ID: PMC2745832]. https://doi.org/10.1167/iovs.08-2228.
-
68.
Siaudvytyte L, Januleviciene I, Daveckaite A, Ragauskas A, Bartusis L, Kucinoviene J, et al. Literature review and meta-analysis of translaminar pressure difference in open-angle glaucoma. Eye (Lond). 2015;29(10):1242-50. [PubMed ID: 26183286]. [PubMed Central ID: PMC4815687]. https://doi.org/10.1038/eye.2015.127.
-
69.
Cerman E, Eraslan M, Cekic O. Age-related macular degeneration and Alzheimer disease. Turk J Med Sci. 2015;45(5):1004-9. [PubMed ID: 26738339].
-
70.
Frost S, Guymer R, Aung KZ, Macaulay SL, Sohrabi HR, Bourgeat P, et al. Alzheimer's disease and the early signs of age-related macular degeneration. Curr Alzheimer Res. 2016;13(11):1259-66. [PubMed ID: 27335042].
-
71.
Keenan TD, Goldacre R, Goldacre MJ. Associations between age-related macular degeneration, Alzheimer disease, and dementia: record linkage study of hospital admissions. JAMA Ophthalmol. 2014;132(1):63-8. [PubMed ID: 24232933]. https://doi.org/10.1001/jamaophthalmol.2013.5696.
-
72.
Goldstein LE, Muffat JA, Cherny RA, Moir RD, Ericsson MH, Huang X, et al. Cytosolic beta-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease. Lancet. 2003;361(9365):1258-65. [PubMed ID: 12699953]. https://doi.org/10.1016/S0140-6736(03)12981-9.
-
73.
Lai SW, Lin CL, Liao KF. Cataract may be a non-memory feature of Alzheimer's disease in older people. Eur J Epidemiol. 2014;29(6):405-9. [PubMed ID: 24752464]. https://doi.org/10.1007/s10654-014-9903-6.
-
74.
Moncaster JA, Pineda R, Moir RD, Lu S, Burton MA, Ghosh JG, et al. Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome. PLoS One. 2010;5(5). e10659. [PubMed ID: 20502642]. [PubMed Central ID: PMC2873949]. https://doi.org/10.1371/journal.pone.0010659.
-
75.
Melov S, Wolf N, Strozyk D, Doctrow SR, Bush AI. Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med. 2005;38(2):258-61. [PubMed ID: 15607908]. https://doi.org/10.1016/j.freeradbiomed.2004.10.023.
-
76.
Ho CY, Troncoso JC, Knox D, Stark W, Eberhart CG. Beta-amyloid, phospho-tau and alpha-synuclein deposits similar to those in the brain are not identified in the eyes of Alzheimer's and Parkinson's disease patients. Brain Pathol. 2014;24(1):25-32. [PubMed ID: 23714377]. [PubMed Central ID: PMC3976129]. https://doi.org/10.1111/bpa.12070.
-
77.
Lai SW, Lin CL, Liao KF, Chang-Ou KC. Increased risk of Parkinson's disease in cataract patients: A population-based cohort study. Parkinsonism Relat Disord. 2015;21(1):68-71. [PubMed ID: 25466927]. https://doi.org/10.1016/j.parkreldis.2014.11.005.
-
78.
Langston JW. The Parkinson's complex: Parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59(4):591-6. [PubMed ID: 16566021]. https://doi.org/10.1002/ana.20834.