June 2018
Volume 59, Issue 7
Open Access
Retina  |   June 2018
Brain-Derived Neurotrophic Factor in Patients With Age-Related Macular Degeneration and Its Correlation With Retinal Layer Thicknesses
Author Affiliations & Notes
  • Merve Inanc Tekin
    Ankara Ulucanlar Eye Training and Research Hospital, Ankara, Turkey
  • Mehmet Ali Sekeroglu
    Ankara Ulucanlar Eye Training and Research Hospital, Ankara, Turkey
  • Canan Demirtas
    Department of Medical Biochemistry, Gazi University, Ankara, Turkey
  • Kemal Tekin
    Department of Ophthalmology, Kars State Hospital, Kars, Turkey
  • Sibel Doguizi
    Ankara Ulucanlar Eye Training and Research Hospital, Ankara, Turkey
  • Serdar Bayraktar
    Ankara Ulucanlar Eye Training and Research Hospital, Ankara, Turkey
  • Pelin Yilmazbas
    Ankara Ulucanlar Eye Training and Research Hospital, Ankara, Turkey
  • Correspondence: Merve Inanc Tekin, Ulucanlar Eye Training and Research Hospital, Ankara, 06240, Turkey; mrvn88@hotmail.com
Investigative Ophthalmology & Visual Science June 2018, Vol.59, 2833-2840. doi:10.1167/iovs.18-24030
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      Merve Inanc Tekin, Mehmet Ali Sekeroglu, Canan Demirtas, Kemal Tekin, Sibel Doguizi, Serdar Bayraktar, Pelin Yilmazbas; Brain-Derived Neurotrophic Factor in Patients With Age-Related Macular Degeneration and Its Correlation With Retinal Layer Thicknesses. Invest. Ophthalmol. Vis. Sci. 2018;59(7):2833-2840. doi: 10.1167/iovs.18-24030.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To determine brain-derived neurotrophic factor (BDNF) levels in serum and aqueous humor (AH) and to assess the relationship between BDNF levels and retinal layer thicknesses in age-related macular degeneration (AMD).

Methods: A total of 48 AMD patients (AMD group) that was composed of twenty-three nonexudative and 25 exudative patients and 26 control subjects (control group) were included in the study. Serum and AH BDNF levels were assessed by ELISA method. Retinal layer thicknesses were calculated by segmentation analysis of optical coherence tomography.

Results: The mean BDNF levels in AH were found to be significantly lower in both the nonexudative and exudative AMD groups than in the control group (P = 0.003 and P < 0.001, respectively). Optical coherence tomography segmentation analysis revealed that the total average retina pigment epithelium thickness was statistically significantly thinner in the nonexudative AMD group compared with the exudative AMD and control groups (P = 0.001 and P = 0.040, respectively). The total average outer nuclear layer (ONL) thicknesses of nonexudative and exudative AMD cases were reduced compared to control group; however, the decrement was statistically significant only in the nonexudative AMD group (P = 0.009). In the correlation analysis of BDNF levels with retinal layer thicknesses, statistically significant correlations exist between BDNF levels of AH with ONL thicknesses in cases of AMD and with retina pigment epithelium thicknesses in the nonexudative AMD group.

Conclusions: BDNF concentrations in AH decreased in the AMD group and this decrease correlates with outer retinal layer thicknesses. Low BDNF levels detected in the AMD group may be insufficient to protect the photoreceptors, resulting in thinning of ONL.

Age-related macular degeneration (AMD) is the most common cause of central vision loss in people over 65 years of age in developed countries.1 The roles of oxidative stress, inflammation, and progressive neurodegenerative cell death leading to retina pigment epithelium (RPE) and photoreceptor loss have been demonstrated in the pathogenesis of AMD.2 
The retina is anatomically and developmentally known as an extension of the central nervous system (CNS); it is composed of retinal ganglion cells (RGCs), which are actually CNS axons that form the optic nerve. Moreover, various eye-specific pathologies such as AMD and glaucoma share characteristics of other CNS pathologies.36 Similarities in the structure of senile plaques observed in Alzheimer's disease (AD) with drusen in AMD have been demonstrated, and it has been suggested that AMD pathophysiology may have common molecular pathways with neurodegenerative disorders of the CNS.46 
Neurotrophic factors are a class of regulatory proteins of nervous tissue that promote the proliferation, differentiation, and functioning of neurons and protect them from apoptosis.7,8 Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that plays an important role in the survival and differentiation of RGCs and in stimulating the development of axons and dendrites in the regenerated RGCs.911 In a large number of studies, the expression of BDNF and its receptors have been shown in different eye structures, including inner and outer layers of the retina, in the cells of the optic nerve head and trabecular meshwork.1012 
Brain and serum concentrations of this neurotrophic factor have been shown to alter in some neurodegenerative disorders such as AD and Huntington's disease.13,14 However, the role of BDNF in the pathophysiology of AMD has not been clearly elucidated. 
Based on the hypothesis that BDNF concentration may change during the retinal degeneration process in AMD, we aimed to determine whether BDNF levels of serum and aqueous humor (AH) differed between the cases with nonexudative AMD, exudative AMD, and age-sex-matched controls and to analyze the relationship between these levels with the retinal layers thicknesses. 
Patients and Methods
Study Design and Patient Selection
This prospective, cross-sectional study was performed between June 2016 and June 2017 at the retina department of a tertiary referral eye hospital. The study protocol was approved by the ethics committee, and the study was carried out in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from patients prior to enrollment. 
Forty-eight eyes of 48 patients with AMD who underwent cataract surgery due to clinically significant cataract during the study period and 26 eyes of 26 patients (control group) having no ocular and systemic disease other than age-related cataract were included in the study. Patients were categorized based on the Age-Related Eye Disease Study classification by using multimodal imaging, including spectral-domain optical coherence tomography (OCT), fundus fluorescein angiography, autofluorescence, and infrared reflectance using the Heidelberg Spectralis (Spectralis HRA-OCT; Heidelberg Engineering, Germany). Only patients in the Age-Related Eye Disease Study group 4 were included in AMD group that was divided into two main groups: 23 cases of nonexudative AMD and 25 cases of exudative AMD. The nonexudative AMD group consisted of the cases with geographic atrophy involving the fovea, and the exudative AMD group consisted of cases with choroidal neovascular membrane scar. Typing of AMD and cataract surgeries were performed by the same experienced retina physician (PY). 
The exclusion criteria for patients and controls were subjects younger than 50 years old, patients with any documented neurologic, psychiatric, neurodegenerative, or neurosurgical problems, those reported any significant ocular/head trauma or surgery, and patients who were on any type of neuro-psycho-pharmacotherapy. Patients having ocular diseases, except AMD, including optic nerve diseases such as glaucoma and ocular hypertension, vitreoretinal interface diseases, and patients with a history of intravitreal injection within the past year and/or history of laser photocoagulation therapy were also excluded. 
Ocular Examination and Evaluation of Retinal Thicknesses
All subjects underwent a comprehensive ophthalmic examination including the best-corrected visual acuity tests using the Snellen chart (20 feet), intraocular pressure measurements, slit-lamp biomicroscopy, and dilated fundus examination. Retinal layers were evaluated by Spectralis OCT Heidelberg Eye Explorer mapping software after optimal pupil dilation. Macular volume cubes centered on the fovea consisting at least 49 B-scans with a minimum of nine automated real-time repetition rate were obtained. 
The autosegmentation mode, which automatically defines the inner and outer boundaries of retinal layers, was first activated in each case. Then, all scans were checked for the segmentation errors, which were described as misrepresentation of the presentative lines in any section of at least one cross-sectional image.15 The need for accurate delineation was noted. If needed, manual adjustment was performed, starting from the innermost layer toward the outer retinal layers. When the software could not draw the boundaries of each layer, boundary lines were manually drawn using the software's caliper function. As a last step, RPE, outer nuclear layer (ONL), and outer plexiform layer (OPL) thicknesses were noted in macular subfields that were determined by the Early Treatment Diabetic Retinopathy Study circle with inner (1-mm diameter) and outer circles (3-mm diameter) as follows: central (within 1 mm), superior, temporal, inferior, and nasal quadrants (Figs. 1, 2). All images were analyzed by two independent experienced retina specialists (MAS and SD). 
Figure 1
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with nonexudative AMD.
Figure 1
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with nonexudative AMD.
Figure 2
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with exudative AMD.
Figure 2
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with exudative AMD.
Assessment of Serum and AH BDNF Levels
Three milliliters of peripheral venous blood was drawn from each participant just before the operation and an AH sample was taken immediately after entering the anterior chamber. The specimens were sampled into serum tubes that were immediately immersed in melting ice. Blood samples were centrifuged for 30 minutes, and then both serum and AH samples were stored at −80°C and analyzed within 6 months from sampling. The author performing BDNF analyses (CD) was blinded to the patient's details. 
The concentration of BDNF was assessed using a Quantikine Human BDNF Immunoassay kit (R&D Systems, Inc., Minneapolis, MN, USA) according to the procedure described in the manufacturer's manual. 
Statistical Analysis
The data obtained from the study were analyzed using the Statistical Package for Social Sciences (SPSS) version 22.0 for Windows (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were presented as mean ± standard deviations, frequency distributions, and percentages. The χ2 test was used in the analysis of categoric variables. Normal distribution of the variables was tested using visual (histogram and probability graphs) and analytic methods (Kolmogorov-Smirnov/Shapiro-Wilk Test). Equality of variances was checked by the Levene test. The 1-way ANOVA, Welch analysis of variance, and Kruskal-Wallis test were used to determine whether there was any significant difference between the three groups. Posthoc tests for pairwise comparisons were also performed. Additionally, Pearson correlation tests were used to investigate the correlations. A probability level of P < 0.05 was considered statistically significant. 
Results
This study included 74 eyes of 74 subjects; 23 of the patients in the nonexudative AMD group, 25 in the exudative AMD group, and the remaining 26 in the control group. No statistically significant difference was observed between groups in terms of age and sex (P > 0.05, for each one). Demographic characteristics of the groups were illustrated in Table 1
Table 1
 
Demographic Characteristics of the AMD and Control Groups
Table 1
 
Demographic Characteristics of the AMD and Control Groups
Table 2 demonstrates the BDNF levels in serum and AH of the participants. There was no statistically significant difference in serum BDNF levels between the groups (P = 0.227). Although BDNF levels of AH were found to be significantly lower in both nonexudative and exudative AMD groups than in the control group (P < 0.001), no statistically significant difference was found between exudative and nonexudative AMD groups (P = 0.875). Additionally, serum and AH levels of BDNF were not statistically significantly correlated (P > 0.05). 
Table 2
 
Comparison of Serum and AH BDNF Levels in the AMD and Control Groups
Table 2
 
Comparison of Serum and AH BDNF Levels in the AMD and Control Groups
Table 3 shows the distribution of total average RPE, ONL, and OPL thicknesses among nonexudative AMD, exudative AMD, and control groups. The total average RPE thickness was statistically significantly thinner in the nonexudative AMD group compared with the exudative AMD and control groups (P = 0.001 and P = 0.040, respectively). The total average ONL thicknesses of nonexudative and exudative AMD cases were reduced compared to control group; however, the decrement was statistically significant only in nonexudative AMD group (P = 0.009). There was no statistically significant difference in OPL thicknesses between the groups (P = 0.373). 
Table 3
 
Comparison of the Total Average Retinal Layers Thicknesses in the AMD and Control Groups
Table 3
 
Comparison of the Total Average Retinal Layers Thicknesses in the AMD and Control Groups
Correlation analysis of BDNF levels in serum and AH with retinal layer thicknesses revealed that there were statistically significant, moderate correlations between BDNF levels of AH with ONL thicknesses in cases with AMD and with RPE thicknesses in the nonexudative AMD group (Table 4). 
Table 4
 
Correlations of Serum and AH BDNF Levels With Retinal Layer Thicknesses
Table 4
 
Correlations of Serum and AH BDNF Levels With Retinal Layer Thicknesses
Discussion
The retina displays similarities to the brain in terms of anatomy, functionality, and immunology. The eye is surrounded by a blood-ocular barrier that shares structures and mechanisms with the blood-brain barrier.16 The anterior chamber of the eye is filled with AH, fluid enriched with anti-inflammatory and immunoregulatory mediators, that is reminiscent of the cerebrospinal fluid.17,18 For all these reasons, the eye is considered an extension of the CNS. 
Beyond the fact that major brain diseases manifest within the eye, several diseases that are unique to the eye display characteristics of neurodegenerative disorders. One of these diseases is AMD, a late-onset neurodegenerative disease, that shares similar risk factors with AD, including aging, hypercholesterolemia, hypertension, obesity, arteriosclerosis, and smoking.19 Both diseases are associated with amyloid deposition.19 Indeed, analysis of drusen that are characteristics of AMD showed that amyloid β accumulation was present in vesicles, especially in patients with advanced AMD.4,20 Additionally, a number of other common proteins have been shown to play a role between drusen and senile plaques, including components of tau, basal membrane proteins, proinflammatory factors, and the complements of complement cascade.21,22 RPE cells have been shown to excrete an amyloid precursor protein and related enzymes to react with amyloid β peptides and secrete proinflammatory and proangiogenic factors.5 Additionally, recent OCT studies have demonstrated that patients with AD had reduced retinal layer thicknesses, especially in the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. Garcia-Martin et al.23 showed that not only were inner retinal layers reduced in AD, but the outer retinal layers were also impaired. Moreover, Kim et al.24 reported that frontotemporal degeneration is associated with outer retinal thinning, and this thinning correlates with disease severity. Considering these OCT findings of neurodegenerative disorders, one possibility is that the retina is vulnerable to the same neuroinflammatory injury that causes neurodegenerative disease in the brain, and similar mechanisms may play a role in the pathogenesis of AMD and AD,4,25 in which the serum level of BDNF has been shown to be affected.14 However, the role of BDNF in the pathophysiology of AMD has not been clearly elucidated. 
In the literature, there are several studies investigating serum BDNF levels and eye diseases such as normal tension glaucoma, primary open angle glaucoma, and diabetic retinopathy.2628 In the only study investigating serum BDNF levels in AMD, serum BDNF levels were found to be significantly higher in AMD patients compared to controls.29 The authors concluded that BDNF release from the CNS may be increased in response to degenerative process in the retina and confounding factors such as stress and exercise might affect their outcome. Our study was the first study investigating the AH levels of BDNF as well as the serum levels in patients with AMD. The different results can be explained with the fact that Afarid et al.29 measured only serum levels of BDNF. Several factors including exercise, intermittent fasting or caloric restriction, dietary modifications, supplements, and drugs can affect BDNF levels in serum.3034 We measured the BDNF level locally in our study to eliminate systemic confounding factors. Our results showed that serum and AH levels of BDNF decreased in both types of AMD groups compared to the control group; however, the decrease was statistically significant only in AH. Moreover, no correlation was determined between BDNF levels of serum and AH in the present study, confirming that serum BDNF levels do not reflect AH levels. 
BDNF can cross the blood-brain barrier35 and is carried by the platelets.36 It has been demonstrated that the concentration of BDNF in serum is nearly equal to the concentration of BDNF found in washed platelet lysates.36 Activated macrophages or lymphocytes could represent additional sources of circulating BDNF.3739 Since BDNF is known to cross the blood-brain barrier in both directions, a substantial part of circulating BDNF might originate from neurons and glia cells of the CNS.35 
The great differences of BDNF levels in serum and AH and the lack of correlation between them suggest that this neurotrophin does not only enter the eye from the bloodstream, but is rather produced in the eye. Indeed, the BDNF expression in different eye structures, including layers of the retina and the optic nerve head,1012 as well as in trabecular apparatus,40 has been shown. Retrograde transport represents another way of BDNF supply to the eye.11 We found statistically significant difference in the BDNF concentration of AH and not in the serum of AMD group, confirming that BDNF is not only transported to the eye from the bloodstream, but is also produced in the eye. There might also be other possible explanations; First, the vascular supply might be reduced in eyes with AMD,41 resulting in a decrease in levels of BDNF derived from serum. Second, Kliffen et al.42 found significant differences in the amount and composition of glycosaminoglycans (GAGs) between macula with and without AMD. Therefore, eyes with AMD might have lower levels of GAGs in the AH; GAGs bind BDNF and are thought to act as reservoirs of BDNF,43 and, third, the inflammatory processes associated with AMD may result in activation of proteases in the AH that destroy BDNF. 
When the differences between the types of the AMD were examined, Afarid et al.29 determined no significant difference in serum BDNF levels between exudative and nonexudative AMD groups. Similarly in the present study, there was no statistically significant difference in both serum and AH levels of BDNF between the nonexudative and exudative AMD groups. 
Animal and laboratory studies have shown that oxidative metabolism, which is required to support the light pathway, could induce or aggravate photoreceptor damage44 and phototoxicity might be a factor in the pathogenesis of AMD.45,46 Neurotrophic factors, including BDNF, have been shown to protect photoreceptors from agents that induce apoptosis45,46 and from phototoxicity.47 Transplantation of cells expressing neurotrophic factors can rescue photoreceptors from different types of toxic agents.48,49 The mature form of BDNF binds the tropomyosin-related kinase B (TrkB) receptor. BDNF-TrkB signaling has diverse physiologic functions, including regulation of photoreceptor development and maintenance.50 BDNF was also consistently reported to promote photoreceptor survival in light damage,45,48,51 although its specific receptors are absent in rod photoreceptors; BDNF and TrkB colocalize in green-red-sensitive cone photoreceptor outer segments.52 This supports the possibility that BDNF might induce signaling in other cells of the retina, thus acting indirectly on photoreceptors.53 Saito et al.54 conducted a study to determine how BDNF protects the photoreceptor against phototoxicity and concluded that BDNF enhanced the expression of TrkB receptors on Müller cells and Müller cells play an important role in the photoreceptor protection from phototoxicity. Regardless of whether BDNF acts directly or indirectly on photoreceptors, this neurotrophin was widely applied to prevent photoreceptor apoptosis.46 In our study, low BDNF levels detected in patients with AMD may be insufficient to protect the photoreceptors from apoptosis and phototoxic damage. Photoreceptor loss is reflected by a loss of ONL thickness, and we found thinning of ONL in both nonexudative and exudative AMD groups. 
When the correlations between BDNF levels of AH and serum with retinal layers thicknesses were examined, statistically significant moderate correlations were found between BDNF levels of AH with ONL and RPE thicknesses in the nonexudative AMD group and with only ONL in the exudative AMD group. The facts that retinal layer thicknesses correlate with the BDNF levels of AH and do not correlate with serum levels suggest that BDNF may be associated with retinal neuronal tissue and the reduction in this neurotrophic factor may be related to the neurodegenerative mechanisms in the retina. 
One of the limitations of the present study is that a healthy control group could not be created because the aqueous sampling was performed from all participants. In the study of Shpak et al.,55 investigating BDNF levels in primary open angle glaucoma, age-related cataract, and healthy subjects, they did not find any significant difference in the BDNF levels of lacrimal fluid (LF) and the serum of healthy controls and patients with cataract, confirming that age-related cataract has little or no effect on the BDNF level in the LF and serum. They also determined a strong correlation of BDNF levels in AH and LF, suggesting that age-related cataract does not influence BDNF level in AH as well, and they suggested that data of patients with age-related cataract could be used as normative data. For this reason, the control group was selected from patients without any ocular or systemic disease other than age-related cataract in present study. In addition, measurement of BDNF levels in vitreous may be thought to be more sensitive. Several studies suggest that AH levels of cytokines reflect their vitreous levels56,57; however, such data is not available for BDNF. This issue needs further examination. Finally, due to the cross-sectional nature of the study, the causal relationship between BDNF levels and AMD cannot be inferred. 
As a conclusion, our study revealed that patients with AMD have decreased concentrations of BDNF and reduced ONL thicknesses. Low BDNF levels detected in the AMD group may be insufficient to protect the photoreceptors, resulting in thinning of ONL. However, whether BDNF in the eye affects the risk for AMD or whether AMD affects the half-life of BDNF should be clarified in further studies. Further analysis of neurotrophic factors in the human eye may be of great importance for clarifying the pathogenesis of AMD and for evaluating the efficacy of any treatment affecting the content of neurotrophic factors in the eye. The understanding of the changes in AMD and its association with other neurodegenerative disorders may also contribute to the diagnosis and treatment of neurodegenerative diseases of the CNS. 
Acknowledgments
The authors alone are responsible for the content and writing of the paper. 
Supported by Ankara regional branch of Turkish Ophthalmological Association. 
Disclosure: M. Inanc Tekin, None; M.A. Sekeroglu, None; C. Demirtas, None; K. Tekin, None; S. Doguizi, None; S. Bayraktar, None; P. Yilmazbas, None 
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Figure 1
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with nonexudative AMD.
Figure 1
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with nonexudative AMD.
Figure 2
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with exudative AMD.
Figure 2
 
Representation of intraretinal layer segmentation and average volume and thickness measurements in an eye with exudative AMD.
Table 1
 
Demographic Characteristics of the AMD and Control Groups
Table 1
 
Demographic Characteristics of the AMD and Control Groups
Table 2
 
Comparison of Serum and AH BDNF Levels in the AMD and Control Groups
Table 2
 
Comparison of Serum and AH BDNF Levels in the AMD and Control Groups
Table 3
 
Comparison of the Total Average Retinal Layers Thicknesses in the AMD and Control Groups
Table 3
 
Comparison of the Total Average Retinal Layers Thicknesses in the AMD and Control Groups
Table 4
 
Correlations of Serum and AH BDNF Levels With Retinal Layer Thicknesses
Table 4
 
Correlations of Serum and AH BDNF Levels With Retinal Layer Thicknesses
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