Retinal Nerve Fiber Layer Thickness in Patients With Alzheimer Disease

The aim of this study was to investigate retinal nerve fiber layer (RNFL) thickness in patients with Alzheimer disease (AD) without visual impairment using spectral domain optical coherence tomography (SD-OCT) and to compare the results with healthy controls. A total of 80 subjects, including 40 patients with early untreated AD (mean age, 69.3 - 4.9 years) and 40 healthy controls (mean age, 68.9 - 5.1 years) were enrolled. Both eyes of patients with AD and controls were imaged using SD-OCT. The average RNFL thickness was significantly less in the AD patients than in controls (65 - 6.2 mm vs 75 - 3.8mm; P = 0.001). There was selective thinning of the RNFL in the superior quadrant, the mean superior quadrant RNFL thickness being 76 - 6.7 mm in AD patients and 105 - 4.8 mm in controls (P = 0.001). In our study, the thickness of RNFL in patient with AD was lower than that of controls. This suggests that SD- OCT has the potential to be used in the early diagnosis of AD as well as in the study of therapeutic agents Further studies are needed to validate this technology as a viable ocular biomarker over time in AD.

Retinal Nerve Fiber Layer Thickness in Patients With Alzheimer Disease Serkan Kirbas, MD, Kemal Turkyilmaz, MD, Omer Anlar, MD, Ahmet Tufekci, MD, Mustafa Durmus, MD Abstract: The aim of this study was to investigate retinal nerve fiber layer (RNFL) thickness in patients with Alzheimer disease (AD) without visual impairment using spectral domain optical coherence tomography (SD-OCT) and to compare the results with healthy controls. A total of 80 subjects, including 40 patients with early untreated AD (mean age, 69.3 ± 4.9 years) and 40 healthy controls (mean age, 68.9 ± 5.1 years) were enrolled. Both eyes of patients with AD and controls were imaged using SD-OCT. The average RNFL thickness was significantly less in the AD patients than in controls (65 ± 6.2 mm vs 75 ± 3.8mm; P = 0.001). There was selective thinning of the RNFL in the superior quadrant, the mean superior quadrant RNFL thick-ness being 76 ± 6.7 mm in AD patients and 105 ± 4.8 mm in controls (P = 0.001). In our study, the thickness of RNFL in patient with AD was lower than that of controls. This suggests that SD- OCT has the potential to be used in the early diagnosis of AD as well as in the study of therapeutic agents. Further studies are needed to validate this technol-ogy as a viable ocular biomarker over time in AD. Journal of Neuro-Ophthalmology 2013;33:58-61 doi: 10.1097/WNO.0b013e318267fd5f © 2012 by North American Neuro-Ophthalmology Society Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia in many countries. Clinically, it is characterized by progressive cognitive impairment and a decline in learning and execu-tive functions (1). Neuropathologic abnormalities in AD include senile plaques that contain amyloid beta (Ab) and neurofibrillary tangles. Neurotransmitter function is also impaired, particularly decreased levels of acetylcholine (2). The entorhinal cortex and hippocampal complex are well known to be the sites of early pathology in AD, but increasing evidence shows that the eye, particularly the retina, is also affected (3). Visual symptoms have been reported in the early stages of AD, including difficulties with reading, finding objects, depth perception, perceiving structure from motion, color recognition, and spatial contrast sensitivity (4). Previous reports have attributed these symptoms to degeneration in the visual cortex. However, there now is increasing evidence that the anterior visual pathways are involved in AD, par-ticularly in the form of optic nerve degeneration and loss of retinal ganglion cells, and it has been suggested that these abnormalities might contribute to visual dysfunction (5,6). Deposits of Ab have been found in the eye and acetylcho-line is known to be crucial to the proper functioning of retinal cells. The mechanism by which Ab might cause death of retinal neurons is not fully understood, but similar mechanisms of neurodegeneration occurring in the brain have been demonstrated in the eye (2,5,7). In the retina, AD-related changes include degeneration and loss of neurons, reduction of retinal nerve fibers, increase in optic disc cupping, retinal vascular narrowing and tortuosity, and functional visual impairment. Optical coherence tomography has been used to study a variety of neurodegenerative diseases (AD, Parkinson disease, amyotrophic lateral sclerosis), multiple sclerosis, and neuro-myelitis optica (8,9). While previous reports have described degeneration of the retinal nerve fiber layer (RNFL) in AD (1,5,6), the aim of our study was to investigate this finding in more detail using spectral domain OCT (SD-OCT). METHODS Subjects This study was conducted at the Neurology and Ophthal-mology Clinic of Rize University School of Medicine, Rize, Eastern Black Sea, Turkey. AD patients were diagnosed Departments of Neurology (SK, OA, AT) and Ophthalmology (KT, MD), Faculty of Medicine, Rize University, Rize, Turkey. The authors report no conflicts of interest. Address correspondence to Serkan Kirbas, Department of Neurology, Faculty of Medicine, Rize University, 53100 Rize, Turkey; E-mail: [e-mail] 58 Kirbas et al: J Neuro-Ophthalmol 2013; 33: 58-61 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. according to the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease Association ("NINCDS-ADRDA") (10). Each patient underwent full neurologic examination and magnetic resonance imaging (MRI) of the brain to ex-clude alternative diagnoses. Patients were included if they met the criteria for minimal cognitive disturbance. Patients were excluded if they had glaucoma (with a diagnosis based on a cup-to-disc ratio of .50%, a cup-to-disc ratio asym-metry between 2 eyes of .20%, corrected intraocular pres-sure [IOP] of .21 mm Hg, and glaucomatous visual field defects), pseudoexfoliation syndrome, high myopia (more than 26.0 diopters), diabetes mellitus, optic disc anomaly, TABLE 1. Mean retinal nerve fiber layer thickness (mm) in patients with AD and healthy controls (mean ± SD) Location Mean RNFL Thickness (mm) AD Controls P Average* 65 ± 6.2 75 ± 3.8 0.001 Nasal 75 ± 2.8 76 ± 2.7 0.964 Temporal 74 ± 6.7 77 ± 7.3 0.752 Superior* 76 ± 6.7 105 ± 4.8 0.001 Inferior 106 ± 11.5 108 ± 8.7 0.769 *P , 0.05. AD, Alzheimer disease; RNFL, retinal nerve fiber layer. FIG. 1. Spectral domain optical coherence tomography of the retinal nerve fiber layer (RNFL) in a patient with Alzheimer disease. The RNFL of the superior quadrant is reduced to the 0-5 percentile for age (red), but the nasal, temporal, and inferior quadrants are normal (green). Kirbas et al: J Neuro-Ophthalmol 2013; 33: 58-61 59 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. age-related macular degeneration, Raynaud phenomenon, sleep apnea, positive family history of glaucoma, history of ocular trauma, optic neuropathy, or were using corticoste-roids or glaucoma medication. In total, 40 patients with newly diagnosed AD who had not yet commenced treatment were studied. The mean age was 69.3 ± 4.9 years (range, 64-80 years), the disease duration was between 6 and 12 months. Patients' Mini- Mental State Examination (MMSE) (11) scores ranged from 18 to 25 of 30, and 22 of the 40 patients were men. The control group consisted of 40 healthy individuals with a mean age of 68.9 ± 5.1 years (range, 60-79 years), of whom 20 were men. The study protocol was approved by the local ethical committee, and all the procedures were performed in accordance with the revised form of the Declaration of Helsinki of 2008. All participants gave informed consent. Patients and controls underwent detailed ocular examina-tion, including measurement of visual acuity, slit-lamp examination of anterior and posterior segments, IOP mea-surement by Goldmann applanation tonometry, central corneal thickness measurement by Pocket Precision ultrasonic pachymeter (Quantel Medical, Clermont-Ferrand, France), color vision testing with Ishihara pseudoisochromatic plates, and visual field testing with automated perimetry (Octopus 900; Haag Streit, Koeniz, Switzerland). After ocular exami-nation and pupillary dilation, subjects underwent SD-OCT. Images were rejected if signal strength was ,8. OCT imaging was performed by the same ophthalmologist. Temporal, na-sal, inferior, and superior quadrant peripapillary RNFL thick-nesses were obtained from the OCT along with a global average using the optic disc 200 · 200 cube scan protocol. Statistical Analysis All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS), version 15.0, for Windows (SPSS, Chicago, IL). Data were expressed as mean ± standard deviation. The normality of the distribution for all variables was assessed by the Kolmogorov-Smirnov test. Student t test was used for normally distributed variables and the Mann-Whitney U test was used for nonparametric variables. Relationships between variables were analyzed by Pearson or Spearman correlation analysis according to the distribution type of the variables. P , 0.05 was considered to be statistically significant. RESULTS There were no significant differences in age or sex between patients with AD and healthy controls (P . 0.05). There were no ocular abnormalities in any of the participants other than simple refractive errors and presbyopia. OCT imaging of the optic nerve and macula was performed on 80 eyes of the 40 AD patients and 40 control subjects. The mean RNFL thickness of the 2 groups is shown in Table 1. The average RNFL thickness in patients with AD was significantly lower than that of healthy controls (65 ± 6.2 mm vs 75 ± 3.8 mm; P = 0.001), and there was selective thinning of the RNFL in the superior quadrant in AD patients (76 ± 6.7 mm vs 105 ± 4.8 mm; P = 0.001) (Fig. 1). Although marginally thinner in patients with AD, there was no signifi-cant difference in RNFL thickness between patients and con-trols in the other 3 quadrants. There was no correlation between MMSE results and OCT measurements. DISCUSSION Our results demonstrate a reduction in the total RNFL thickness of AD patients compared with healthy controls. This was primarily because of the thinning of the RNFL in the superior quadrant. Using lower resolution time domain OCT, previous studies also noted a significant reduction in the circumpapillary RNFL thickness in patients with AD TABLE 2. Published reports of RNFL thickness in AD patients Author (Reference) AD Patients (n) OCT Technique Average RNFL Thickness (mm) Superior RNFL Thickness (mm) Inferior RNFL Thickness (mm) Nasal RNFL Thickness (mm) Temporal RNFL Thickness (mm) Iseri et al (13) 14 TD 87.46 ± 23.78* 112.64 ± 35.32* 103.10 ± 33.4* 63.57 ± 19.09* 64.92 ± 17.7 Berisha et al (5) 9 TD 98.76 ± 10.9 92.2 ± 21.6* 117.0 ± 15.3 65.7 ± 15.1 67.0 ± 15.0 Paguet et al (12) 12 TD 78.8 ± 4.9* 118.5 ± 35.3* 112.6 ± 25.3* 62.6 ± 18.3* 64.3 ± 16.4* Ci et al (14) 12 TD 84.2 ± 10.6 115.09 ± 14.05* 126.08 ± 15.8 77.6 ± 4.9 78.4 ± 6.4 Kesler et al (6) 30 TD 84.7 ± 10.6* 99.0 ± 18.0* 110.1 ± 19.1 66.8 ± 14.5 61.7 ± 10.9 Current study 40 SD 65 ± 6.2* 76 ± 6.7* 106 ± 11.5 75 ± 2.8 74 ± 6.7 *P , 0.05 (compared with controls). AD, Alzheimer disease; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer; SD, spectral domain; TD, time domain. 60 Kirbas et al: J Neuro-Ophthalmol 2013; 33: 58-61 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. compared with age-matched controls, albeit in relatively small numbers of patients (5,6,12-14) (Table 2). Similar to our findings, these reports documented reduction of RNFL thickness most prominently in the superior quadrant, consistent with an inferior visual field defect often found in AD patients. The explanation for this pattern of visual field loss has been primary involvement of axons from the superior retina to the cuneal gyrus of the primary visual cortex, with relative spacing of axons from the inferior retina to the lingual gyrus. In a histopathologic study of AD, Armstrong (15) found a greater density of senile plaques and neurofibrillary tangles in the cuneal gyrus than in the lingual gyrus. However, the OCT finding of superior RNFL thinning suggests that the field deficits in AD patients may actually be related to neuronal degenera-tion in the retina. The cause of RNFL thinning in AD is probably due to death of retinal ganglion cell axons as well as retrograde degeneration from loss of cortical neurons. Ab has been implicated in the pathogenesis of AD in the brain (3): it has long been known that Ab aggregates are toxic to cortical neurons both in vitro and in vivo. Retinal neurons have also been shown to be sensitive to the neurotoxicity of Ab, and recent studies have suggested that Ab-induced neurotoxicity may be implicated in glaucoma and macular degeneration (2). It is possible that AD patients may exhibit retinal abnormalities because of the deposition of amyloid peptide in retinal tissue (2,3). This is supported by the findings of Koronyo-Hamaoui et al (16) in both patients and a mouse model of AD. We included patients with early-stage AD and who were newly diagnosed, and we believe this is important for 2 reasons. First, we suspected that differences might not be so obvious in the later stages of AD as RNFL thickness decreases with age (2). Second, we excluded the possible effect of medications such as donepezil, memantine, and galantamine. These drugs may have a modest overall benefit in stabilizing and slowing the progression of the disease (17). Evaluating AD patients with SD-OCT may have important clinical implications. This technology could provide a rapid noninvasive method of early detection of AD. This would permit institution of neuroprotective therapies early in the course of the disease. 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