November 2018
Volume 7, Issue 6
Open Access
Articles  |   November 2018
Effects of Age, Race, and Ethnicity on the Optic Nerve and Peripapillary Region Using Spectral-Domain OCT 3D Volume Scans
Author Affiliations & Notes
  • Linda Yi-Chieh Poon
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
  • Hussein Antar
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    University of Massachusetts Medical School, Worcester, MA, USA
  • Edem Tsikata
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
  • Rong Guo
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Department of Medicine, University of California, Los Angeles, CA, USA
  • Georgia Papadogeorgou
    Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
    Department of Statistical Science, Duke University, Durham, NC, USA
  • Madeline Freeman
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Smith College School for Social Work, Northampton, MA, USA
  • Ziad Khoueir
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Beirut Eye and ENT Specialist Hospital, Université Saint-Joseph Medical School, Beirut, Lebanon
  • Ramon Lee
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    University of Southern California Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • Eric Shieh
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
  • Huseyin Simavli
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    Department of Ophthalmology, Pamukkale University, School of Medicine, Denizli, Turkey
  • Christian John Que
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
    University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines
  • Johannes F. de Boer
    LaserLaB, Department of Physics and Astronomy, Vrije Universiteit, Amsterdam, The Netherlands
    Department of Ophthalmology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
  • Teresa C. Chen
    Department of Ophthalmology, Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
  • Correspondence: Teresa C. Chen, Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Glaucoma Service, 243 Charles Street, Boston, MA 02114, USA. e-mail: teresa_chen@meei.harvard.edu 
Translational Vision Science & Technology November 2018, Vol.7, 12. doi:10.1167/tvst.7.6.12
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      Linda Yi-Chieh Poon, Hussein Antar, Edem Tsikata, Rong Guo, Georgia Papadogeorgou, Madeline Freeman, Ziad Khoueir, Ramon Lee, Eric Shieh, Huseyin Simavli, Christian John Que, Johannes F. de Boer, Teresa C. Chen; Effects of Age, Race, and Ethnicity on the Optic Nerve and Peripapillary Region Using Spectral-Domain OCT 3D Volume Scans. Trans. Vis. Sci. Tech. 2018;7(6):12. doi: 10.1167/tvst.7.6.12.

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

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Abstract

Purpose: To evaluate the effects of age, race, and ethnicity on the optic nerve and peripapillary retina using spectral-domain optical coherence tomography (SD-OCT) three-dimensional (3D) volume scans in normal subjects.

Methods: This is a cross-sectional study performed at a single institution in Boston. All patients received retinal nerve fiber layer (RNFL) scans and an optic nerve 3D volume scan. The SD-OCT software calculated peripapillary RNFL thickness, retinal thickness (RT), and retinal volume (RV). Custom-designed software calculated neuroretinal rim minimum distance band (MDB) thickness and area.

Results: There were 272 normal subjects, including 175 whites, 40 blacks, 40 Asians, and 17 Hispanics. Rates of age-related decline were 2.3%, 2.0%, 1.7%, 3.3%, and 4.3% per decade for RNFL, RT, RV, MDB neuroretinal rim thickness, and MDB area, respectively. The RNFL was most affected by racial and ethnic variations, with Asians having thicker global, superior, and inferior RNFL, Hispanics having thicker inferior RNFL, and blacks having thinner temporal RNFL, compared to whites. For MDB thickness and area, Asians had smaller nasal values and blacks had smaller temporal values. Peripapillary RT and RV parameters were not influenced by race and ethnicity.

Conclusions: All of the parameters exhibited age-related declines. RNFL, MDB thickness, and MDB area demonstrated racial and ethnic variations, while peripapillary RT and RV did not.

Translational Relevance: This study demonstrates that both normal aging and ethnicity affect several novel 3D OCT parameters used to diagnose and monitor glaucoma (i.e., RT, RV, and MDB), and this should be factored in when making clinical decisions based on these parameters.

Introduction
Advances in spectral-domain optical coherence tomography (SD-OCT)13 have established optical coherence tomography (OCT) as an integral part of clinical care in glaucoma today.46 This SD-OCT technology not only allows for detailed visualization of the optic nerve and peripapillary retina but also allows for quantifiable and reproducible measurements of these structures.1,710 
The most common OCT parameter used for evaluating glaucomatous structural change is peripapillary two-dimensional (2D) retinal nerve fiber layer (RNFL) thickness,1113 which is typically obtained along a 3.45 to 3.46 mm diameter circle centered on the disc. However, as glaucoma progresses, the RNFL reflectivity decreases,14 causing the border between the RNFL and ganglion cell layer to become less distinct, leading to segmentation errors of the RNFL border. As a result, the artifact rate for peripapillary RNFL scans has been reported to be as high as 19.9%15 to 46.3%.16 Therefore, there is a need for other parameters that can be reliably identified while also yielding high diagnostic performance. Several newer parameters of the macula and optic nerve head have been investigated and include macular retinal thickness (RT),17 macular inner RT,18 and the neuroretinal rim parameter Bruch's membrane opening-minimum rim width (BMO-MRW).19 This paper, however, focuses on other, newer parameters, which can be generated from a three-dimensional (3D) volume scan of the optic nerve and its peripapillary region. These 3D optic nerve volume scan parameters include the following: peripapillary RT within an annular region,20 peripapillary retinal volume (RV) within an annular region,21 neuroretinal rim minimum distance band (MDB) thickness,1,22,23 and neuroretinal rim MDB area.23 
For glaucoma diagnosis, OCT parameters that can be derived from a 3D optic nerve volume scan have been shown to have similar or better diagnostic capability compared to RNFL thickness measurements while sometimes having fewer artifacts.2023 For example, peripapillary RT and RV have diagnostic performance that is comparable to or better than RNFL thickness.20,21 Furthermore, peripapillary RT and RV may have an advantage over RNFL thickness because retinal measurements may have fewer segmentation difficulties, as can be seen with glaucomatous RNFL reflectivity loss and peripapillary atrophy (PPA).20,21 Similar to the BMO-MRW, the MDB is a 3D neuroretinal rim parameter that quantifies the amount of tissue in the neuroretinal rim band, which is delimited internally by the retinal surface and externally by the OCT-derived disc border, based on the termination of the retinal pigment epithelium/Bruch's membrane (RPE/BM) complex.1,22,23 The MDB thickness has similar or better diagnostic capability compared to RNFL thickness for glaucoma and performs significantly better in the nasal region,22,23 which is a region where the RNFL parameter typically yields poorer diagnostic performance.11,13 
Because new glaucoma OCT parameters derived from 3D volume scans may have the same or better diagnostic capability compared to the traditional 2D RNFL thickness parameter, it is important to know the normal variations of these new 3D volume scan–derived parameters. The primary hypothesis of this study is that age, race, and ethnicity can affect the following OCT parameters in a normal population: RNFL thickness, neuroretinal rim parameters (i.e., MDB thickness and area), and peripapillary retinal parameters (i.e., RT and RV). 
Methods
Subjects
Study subjects were prospectively recruited between 2009 and 2015 from the Glaucoma Service of the Massachusetts Eye and Ear Infirmary (MEEI) as a part of the prospective Spectral Domain Optical Coherence Tomography in Glaucoma (SIG) study.7,11,16,2023 Informed consents were obtained from all study patients. The study methods were approved by the MEEI Institutional Review Board, adhered to the tenets of the Declaration of Helsinki, and was compliant with the Health Insurance Portability and Accountability Act. 
All subjects had a comprehensive eye examination, which included history, visual acuity (VA), refraction, intraocular pressure (IOP), slit lamp biomicroscopy, dilated fundus exam, visual field (VF) testing (Swedish Interactive Threshold Algorithm 24-2 test, Humphrey VF Analyzer; Carl Zeiss Meditec Inc., Dublin, CA), color disc photography (Visucam Pro NM; Carl Zeiss Meditec Inc.), and SD-OCT imaging (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). 
Subjects were included in the study if they satisfied all of the following inclusion criteria: (1) age >18 years; (2) clinically normal eye exam except for mild cataracts; (3) IOP of ≤ 21 mm Hg; (4) best-corrected VA of ≥ 20/40; (5) normal VF results defined by a Glaucoma Hemifield Test that is within normal limits and without a pattern standard deviation that has a probability of occurring in <5% of the normal population; and (6) spherical equivalent between −5 and +5 diopters. 
Subjects were excluded from the study if they had (1) unreliable VF test results with >33% fixation loss, >20% false-negative results, or >20% false-positive results; (2) any neurologic disease or use of systemic medication that could produce VF defects; (3) OCT image quality score (Q) of <15 on the RNFL circle scan printout. 
Subjects were categorized into the following racial and ethnic categories: white, black, Asian, and Hispanic. The category “black” includes Hispanic blacks, while Hispanic refers only to Hispanic whites. In all cases, racial and ethnic classification are based on self-identification. 
Spectralis OCT Scanning
After pupillary dilation, each subject underwent OCT imaging and received two scans centered on the optic nerve: (1) a standard 12° circular scan, which equates to a retinal diameter of approximately 3.46 mm in an eye with typical corneal curvature and axial length, and (2) a 20° × 20° volume scan consisting of 193 equidistant horizontal frames with the automatic real time set to 3. 
Analysis of Peripapillary RNFL Thickness and Peripapillary Annulus Parameters
Peripapillary RFNL thickness was determined by the instrument's built-in software, which automatically segments the internal limiting membrane (ILM) and the posterior RNFL border and then determines thickness values as the distance between these two layers (Fig. 1A). The global and four-quadrant RNFL thickness values were used for analysis. 
Figure 1
 
Peripapillary and neuroretinal parameters investigated in this study. (A) Sample of RNFL scan centered on the optic nerve, from which RNFL thickness is obtained for analysis. (B) Illustration of how peripapillary RT and RV were obtained from volume scans of the optic nerve and a RT color map superimposed on the infrared reflectance (IR) image of the peripapillary region, with a circular grid with circle diameters of 1, 2.22, and 3.45 mm manually centered on the optic nerve. The RT and RV values within the outer annulus (2.22–3.45 mm) were analyzed. (C) The OCT-based disc border (red dots) superimposed on the IR image of the peripapillary region and a 3D image of the neuroretinal rim MDB generated by our customized software. On the 3D image, yellow lines are the segmented internal limiting membrane layer. The red dots represent the OCT-based disc border, which correlates with the termination of the RPE/BM complex. The blue dots represent the cup surface points closest to the corresponding OCT-based disc border, between which forms the MDB (blue band).
Figure 1
 
Peripapillary and neuroretinal parameters investigated in this study. (A) Sample of RNFL scan centered on the optic nerve, from which RNFL thickness is obtained for analysis. (B) Illustration of how peripapillary RT and RV were obtained from volume scans of the optic nerve and a RT color map superimposed on the infrared reflectance (IR) image of the peripapillary region, with a circular grid with circle diameters of 1, 2.22, and 3.45 mm manually centered on the optic nerve. The RT and RV values within the outer annulus (2.22–3.45 mm) were analyzed. (C) The OCT-based disc border (red dots) superimposed on the IR image of the peripapillary region and a 3D image of the neuroretinal rim MDB generated by our customized software. On the 3D image, yellow lines are the segmented internal limiting membrane layer. The red dots represent the OCT-based disc border, which correlates with the termination of the RPE/BM complex. The blue dots represent the cup surface points closest to the corresponding OCT-based disc border, between which forms the MDB (blue band).
Peripapillary RT and RV values were obtained from 3D volume scans of the optic nerve. To calculate RT and RV within an annular region, Figure 1B shows how the Early Treatment Diabetic Retinopathy Study (ETDRS) circular grid was manually centered over the optic nerve using the machine's built-in software (Heidelberg Eye Explorer, version 1.9.10.0; Heidelberg Engineering). In the example shown (Fig. 2A), the retinal borders were segmented in red, with the anterior retinal border being the ILM and the posterior retinal border being Bruch's membrane.24 Using the ETDRS circular grid with diameters of 1, 2.22, and 3.45 mm, peripapillary RT and RV values within the outer annulus of this ETDRS circle grid (i.e., inner circle diameter 2.22 mm and outer circle diameter 3.45 mm; Fig. 1B) were obtained for analysis. This annulus diameter was chosen based on our previous work,20,21 since it yielded higher diagnostic capability for glaucoma compared to a larger annulus of 3 to 6 mm and was less affected by the presence of PPA, compared to a smaller annulus of 2 to 3 mm. The global and four-quadrant values were used for analysis. Global RT values were determined by averaging RT for the four quadrants, and global RV values were generated by the OCT's built-in software. 
Figure 2
 
Scatter plots of age versus the global values of three peripapillary parameters and two neuroretinal rim parameters. The three peripapillary parameters are (A) RNFL thickness, (B) RT, and (C) RV. The two neuroretinal rim parameters are (D) MDB thickness and (E) MDB area.
Figure 2
 
Scatter plots of age versus the global values of three peripapillary parameters and two neuroretinal rim parameters. The three peripapillary parameters are (A) RNFL thickness, (B) RT, and (C) RV. The two neuroretinal rim parameters are (D) MDB thickness and (E) MDB area.
Analysis of Neuroretinal Rim MDB Parameters
The methods and custom-designed software used to determine MDB thickness and area from 3D optic nerve volume scans were described in prior studies.22,23 In brief, the custom-designed software was developed at MEEI and used Open Source Computer Vision (version 2.4.3; OpenCV, Willow Garage, Menlo Park, CA) and the Insight Segmentation and Registration Toolkit (ITK, version 4.3; Insight Software Consortium, Kitware Inc., Clifton Park, NY) libraries. This software automatically segments the ILM and the RPE/BM complex, and the segmented images were manually reviewed and corrected for errors. The software then determines the OCT-derived disc margin (i.e., termination of RPE/BM), which is represented by 100 points that are 3.6° apart. The program identifies the 100 closest corresponding points on the ILM, creating a 3D ribbon that is defined as the MDB (Fig. 1C). MDB thickness was calculated as the average of the shortest distance between corresponding points on the ILM and RPE/BM termination. MDB area takes into account the multidirectionality assumed by the 3D MDB ribbon, and the MDB area is calculated from the summation of the areas of triangles formed by two adjacent points on the ILM or RPE/BM termination and their corresponding shortest point on the ILM or RPE/BM.23 Global and quadrant MDB neuroretinal rim thickness and area values were obtained for analysis. 
Statistical Analysis
One eye from each subject was chosen randomly to be included in the analysis. Statistical analyses were performed using statistical software (SAS 9.4; SAS Institute Inc., Cary, NC, and R 3.2.3). Descriptive statistics were used to report continuous variables as mean ± the standard deviation. Categorical variables were reported as percentages. ANOVA was used for comparison of the mean values between different ethnic groups. The effects of age, race, and ethnicity on each of the parameters were analyzed using multivariate analysis that adjusted for gender and refraction. P < 0.05 was considered statistically significant. 
Results
OCT images from 272 eyes of 272 subjects were analyzed (Table 1). The average age of subjects was 57.8 ± 15.7 years with a range of 18 to 94 years. All subjects were healthy as defined by the inclusion criteria. The majority of subjects were white (64.3%). The Asian population (n = 40) comprised 15 Chinese, 3 Korean, 3 Japanese, 9 Indian, 5 Vietnamese, and 5 unclassified Asian subjects. 
Table 1
 
Summary of Patient Demographics
Table 1
 
Summary of Patient Demographics
Table 2 summarizes the global and quadrant mean values for peripapillary RNFL thickness, peripapillary RT, peripapillary RV, neuroretinal MDB thickness, and neuroretinal rim MDB area. The mean RNFL thickness and neuroretinal rim parameters in general followed the ISNT rule and were thickest in the inferior quadrant, followed by the superior, nasal, and temporal quadrants. Peripapillary RT and RV showed similar trends of having thicker values in the vertical quadrants and thinner values in the horizontal quadrants. 
Table 2
 
Mean Normal Values for OCT Neuroretinal and Peripapillary Parameters: Rates of Age-Related Decline by Absolute Values and by Percentages
Table 2
 
Mean Normal Values for OCT Neuroretinal and Peripapillary Parameters: Rates of Age-Related Decline by Absolute Values and by Percentages
Table 2 also shows the absolute slope for changes with age after adjusting for race and refraction, for all of the parameters. Regionally, RNFL thickness had the highest rate of age-related change in the superior quadrant (−0.35 μm per year, P < 0.001). For RT, age-related change was greatest in the inferior quadrant (−0.79 μm per year, P < 0.001). Peripapillary RV showed similar rates of decline in most of the quadrants (−0.001 mm3 per year, P < 0.001) but decreased at a slower rate in the temporal quadrant (−0.0003 mm3 per year, P = 0.004). For the neuroretinal rim, MDB thickness demonstrated the highest rate of age-related change in the inferior quadrant (−1.27 μm per year, P < 0.001), while for MDB area, similar rates of decline were found in the superior, inferior, and nasal quadrants (−0.002 μm per year for all three quadrants; all P < 0.05). Temporal quadrant changed the least with age in all of the parameters and in general demonstrated no statistically significant relationship with age. 
Figure 2 shows that the global values for peripapillary RNFL thickness, peripapillary RT, peripapillary RV, neuroretinal rim MDB thickness, and neuroretinal rim MDB area all decreased significantly with age. With respect to the population mean, the rates of age-related change correspond to a decline of 2.3% per decade for RNFL thickness, a 2.0% decline per decade for peripapillary RT, and a 1.7% decline per decade for peripapillary RV (Table 2). While at the neuroretinal rim, MDB thickness exhibits a 3.3% decrease per decade, and the MDB area demonstrates a 4.3% decrease per decade (Table 2). 
Figure 3 shows the mean values of peripapillary RNFL thickness, peripapillary RT and RV, and MDB neuroretinal rim thickness and area, according to race and ethnicity. Highest variation is present for RNFL thickness values, with the global and most quadrant values showing significant differences between the racial and ethnic groups, while for MDB thickness and area, significant differences between racial and ethnic groups were present for the nasal and temporal quadrant. The least variation is observed for peripapillary RT and RV values, in which no statistical differences were detected for the global and quadrant values for either of these parameters. 
Figure 3
 
Bar graphs showing the racial and ethnic variations in the mean and standard deviation values of three peripapillary retinal parameters and two neuroretinal rim parameters. Asterisks represent significant difference (P < 0.05) when compared to white. Error bars represent standard deviation.
Figure 3
 
Bar graphs showing the racial and ethnic variations in the mean and standard deviation values of three peripapillary retinal parameters and two neuroretinal rim parameters. Asterisks represent significant difference (P < 0.05) when compared to white. Error bars represent standard deviation.
Using whites as the reference group, multivariate analysis that adjusted for age and refraction showed that race and ethnicity significantly affected expected normal RNFL thickness values and MDB neuroretinal rim parameters, but not peripapillary retinal parameters (Table 3). RNFL thickness was most affected by race and ethnicity, in which blacks had thinner RNFL thickness values in the temporal quadrant; Asians had thicker global, superior, and inferior RNFL thickness values; and Hispanic patients had thicker inferior RNFL thickness values. For the neuroretinal rim parameter, blacks had thinner temporal MDB thickness values and smaller MDB areas, and Asians had smaller MDB thickness and MDB area values in the nasal quadrant. There was no significant racial or ethnic influence on 3D peripapillary retinal parameters. 
Table 3
 
Linear Regression Analysis Showing the Effects of Race and Ethnicity on the Global and Regional Values of Three Peripapillary Retinal Parameters and Two Neuroretinal Rim Parametersa,b
Table 3
 
Linear Regression Analysis Showing the Effects of Race and Ethnicity on the Global and Regional Values of Three Peripapillary Retinal Parameters and Two Neuroretinal Rim Parametersa,b
Discussion
As new parameters from 3D OCT optic nerve volume scans emerge for the diagnosis and long-term monitoring of glaucoma patients, it is important to characterize the effects of aging on these parameters and to understand how these parameters are affected by differing races and ethnicities. Our study is, to our knowledge, the first to comprehensively assess how aging, race, and ethnicity affect not only the traditional 2D RNFL thickness parameter but also the newer 3D OCT volume scan parameters, such as neuroretinal rim MDB thickness, neuroretinal rim MDB area, peripapillary RT, and peripapillary RV, all of which can be derived from a single 3D volume scan of the optic nerve head. 
As the most commonly used OCT parameter for the management of glaucoma, the relationship between RNFL thickness and aging in the normal population has been thoroughly investigated in past studies, with decline rates of −1.5 to −3.7 μm per decade being reported.2532 In our study, we found a decline rate of −2.0 μm per decade for global RNFL thickness (Table 2), compatible with what was reported in previous studies. With regard to the quadrants, RNFL thickness has been found to be most strongly affected by age in the superior25,27,29,33 and inferior26,32 quadrants, similar to the findings in this study, in which highest rates of RNFL age-related change were found in the superior (−3.5 μm per decade, Table 2) and the inferior quadrants (−2.7 μm per decade, Table 2). 
To our knowledge, although the age-related changes in the macular retina have been extensively studied in the past,29,3440 the effect of aging on the peripapillary retina has not been comprehensively investigated previously. Different from prior studies on global macular retinal thickness, which reported rates of age-related thinning of −1.9 to −4.2 μm per decade,29,36,38 our study found that global peripapillary RT had age-related decline at a rate of −6.3 μm per decade (Table 2). Although our results are higher than the rates previously reported for the macular retinal thickness, our results are consistent with the fact that a higher proportion of RNFL exists in the peripapillary region, as the RNFL is normally thinner the farther one is from the optic nerve.31,41 Similar to peripapillary RT, our study also found a higher global peripapillary RV decline of −0.03 mm3 (−1.7%) per decade (Table 2), compared to other studies of the macular retina that reported global thinning rates corresponding to −0.6%36 to −0.8%38 per decade. For quadrants, our study found that the highest age-related change occurred in the superior and inferior quadrants for both peripapillary RT and RV (Table 2). This similar trend was also observed for RNFL thickness in our study, and also in other studies,25,27,29,33 and shows that the age-related thinning in the peripapillary retina may be associated with the thinning of the RNFL. Therefore, our data not only showed that there are distinct differences between rates of age-related thinning in the peripapillary retina compared to previously reported rates for the macular retina,29,3638 it also showed that comprehensive evaluation of age-related changes in both the peripapillary RNFL and the optic nerve fibers requires analyzing the peripapillary retina and not just the macular retina. 
Analysis of neuroretinal rim MDB parameters also showed that the neuroretinal rim demonstrates significant changes with age. The neuroretinal rim MDB, as described in our previously published studies,22,23 is an OCT-derived parameter that represents an encircling band of tissue composed of the retinal nerve fibers as they exit the eye. The neuroretinal rim MDB thickness and area are derived from 3D optic nerve volume scans and provide a surrogate measure of the total amount of nerve tissue in the optic nerve. The MDB determines a neuroretinal rim band and is similar to the BMO-MRW,19,42 but the MDB differs from the BMO-MRW by defining the OCT-derived disc border as the RPE/BM complex versus just the Bruch's membrane opening.22,23 Future studies to directly compare the age-related changes of MDB versus BMO-MRW would be interesting. Past histology studies of the optic nerve have demonstrated a loss of 2.9%43 to 3.7%44 of axons in the optic nerve per decade, which were comparable to the rates of age-related changes we observed in this study for global MDB thickness at −3.3% per decade, and for global MDB area at −4.3% per decade (Table 2). 
Comparison between the global parameters showed that peripapillary parameters (i.e., RNFL thickness at −2.3% per decade; peripapillary RT at −2.0% per decade; peripapillary RV at −1.7% per decade) appeared to proportionally have slower rates of age-related decline than neuroretinal rim parameters (i.e., MDB thickness at −3.3% per decade; MDB area at −4.3% per decade) (Table 2). Similar trends were observed by Chauhan et al.32 in which a loss of 2.1% per decade was found for RNFL thickness, while BMO-MRW had a loss of 4.0% per decade.32 The different rates of age-related changes may be explained by the different proportions of retinal ganglion cell (RGC) axons, which exhibit atrophic changes with aging, to supporting glial cells, which have self-renewal properties and remain activated with aging,45,46 in the peripapillary retina versus the neuroretinal rim. In the neuroretinal rim, which is the region represented by the MDB, about 94% are RGC axons and about 5% are glial contents.47 In contrast, in the peripapillary retina, the proportion of glial contents in the nerve bundles is about 18% to 35%.48 Thus, the higher rate of decline observed in the MDB parameters may reflect a higher proportion of RGC axons to glial cells within the neuroretinal rim compared to the peripapillary retina. The clinical relevance of these findings is that through comprehensive 3D analysis of the peripapillary region and the optic nerve, we found that age-related thinning occurs at differing rates depending on the structure being evaluated, and that in normal eyes, the neuroretinal rim demonstrates considerably higher age-related thinning compared to the peripapillary retina and RNFL, which should be regarded as a normal aging process and not mistaken for glaucomatous disease progression. 
Our study also found racial and ethnic differences in the OCT parameters that were derived from 3D optic nerve volume scans. For the traditional 2D RNFL thickness parameter (Fig. 3), we found that Hispanics had thicker global and inferior RNFL values compared to whites, which is consistent with the past literature25,34,49 and may be associated with larger discs in Hispanics compared to whites,50,51 resulting in thicker RNFL measurements in Hispanics due to the fixed scan circle being closer to the disc border. In our study, we also found that blacks had thinner temporal RNFL thickness (Fig. 3) compared to whites. This is also consistent with what was previously reported in the literature.34,52 The least racial and ethnic variations were observed for the 3D peripapillary retinal parameters, RT and RV (Fig. 3; Table 3). We suspect that racial and ethnic variations in disc size may have less effect on peripapillary retinal parameters (i.e., RT and RV) compared to the RNFL thickness parameter because any effects of varying disc size may be blunted with peripapillary retinal parameters, which evaluate a wider peripapillary region (i.e., a 2.22 to 3.45 mm annulus) compared to the traditional 2D RNFL thickness parameter. With regard to the neuroretinal rim, we found that, compared to whites, Asians had smaller nasal MDB thickness and area values, while blacks had thinner temporal MDB thickness and area values. This may be due to the relatively larger disc sizes and cupping found in normal Asians and blacks compared to whites.50,51 Since the MDB measures neuroretinal rim tissue, this parameter may be more greatly affected by racial and ethnic variations in disc morphology. In summary, we found that the RNFL thickness parameter was most affected by racial variations, with blacks having thinner temporal RNFL; Asians having thicker global, superior, and inferior RNFL; and Hispanics having thicker inferior RNFL. For MDB thickness and area, Asians had smaller nasal MDB thickness and area values and blacks had smaller temporal MDB thickness and area values. Peripapillary RT and RV parameters were not affected by race and ethnicity. Thus, our findings suggest that, clinically, when deciding whether an observed thinning in the RNFL or neuroretinal rim is attributable to glaucoma or not, race and ethnicity should be factored in since artifactual thinning may be attributable to racial and ethnic differences, and this highlights the importance of race- and ethnicity-specific normative databases for these OCT parameters. Peripapillary RT and RV, on the other hand, appears not to be affected by race and ethnicity and thus may be a more useful parameter for monitoring disease progression in a clinical setting where patients of many different races and ethnicities are being examined. BMO-MRW is similar to the MDB OCT parameter and may be useful in a multiracial clinical setting because BMO-MRW was found to have no racial variations in a study comparing subjects of African descent versus European descent.53 
Our study had a number of limitations. One of the limitations was its cross-sectional study design, where individual variability and sampling bias might have contributed to results that are not necessarily universally generalizable. A second limitation was that there was not an even distribution of races and ethnicities in the study, which included predominantly whites (Table 1). Our study results would therefore need to be interpreted with caution, especially for races and ethnicities with small patient numbers; however, our study findings of racial and ethnic differences in RNFL thickness are consistent with findings in prior studies.25,34,49,52 Therefore, by extrapolation, this study's findings of the influence of race and ethnicity on certain 3D OCT parameters may still be valid. Another limitation is the categorization of the Asian population in this study, which is comprised of subjects who are Chinese, Korean, Japanese, and Indian. Although often present in the ophthalmic literature, the term “Asian” carries with it an assumption of relative genetic homogeneity, when in fact this may capture a heterogeneous group of people. A better study would have included larger numbers of each Asian subgroup, but the current study of only 40 Asian subjects does not have adequate numbers for subgroup analysis. Additionally, all of the normal subjects in this study were recruited from a university-based glaucoma clinic, and a larger population-based study might have found different results. However, our normal study subjects included a diversity of races and ethnicities similar to the racial composition of the Boston Metropolitan area and had an average cup-to-disc ratio of 0.48, which is not unexpected with a study population with some black and Hispanic subjects, whose cup-to-disc ratios are normally up to 0.6. 
In conclusion, this study revealed significant age-related decline in both MDB neuroretinal rim and peripapillary retinal parameters (i.e., RT and RV), with the neuroretinal rim MDB parameters demonstrating the highest rates of age-related decline compared to the other parameters. In terms of normal racial and ethnic variations, RNFL thickness and neuroretinal rim parameters demonstrated the most variation among different races and ethnicities, while the peripapillary RT and RV were not affected by racial and ethnic differences. This study underscores the importance of factoring in age-related changes and ethnic variations when making clinical decisions based on neuroretinal rim and peripapillary retinal OCT parameters in glaucoma management. 
Acknowledgments
Supported by American Glaucoma Society Mid-Career Award (TCC), Massachusetts Lions Eye Research Fund (TCC), Fidelity Charitable Fund (TCC), Harvard Catalyst Grant (TCC), National Institutes of Health Grant (TCC; UL RR025758), and Department of Defense Small Business Innovation Research (TCC; DHP15-016). 
Disclosure: L.Y.-C. Poon, None; H. Antar, None; E. Tsikata, None; R. Guo, None; G. Papadogeorgou, None; M. Freeman, None; Z. Khoueir, None; R. Lee, None; E. Shieh, None; H. Simavli, None; C.J. Que, None; J.F. de Boer, Center for Biomedical Optical Coherence Tomography Research and Translation Scientific Advisory Board Chair, Harvard Medical School (S), licenses to NIDEK, Inc., Terumo Corporation, Ninepoint Medical, and Heidelberg Engineering (F); T.C. Chen, None 
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Figure 1
 
Peripapillary and neuroretinal parameters investigated in this study. (A) Sample of RNFL scan centered on the optic nerve, from which RNFL thickness is obtained for analysis. (B) Illustration of how peripapillary RT and RV were obtained from volume scans of the optic nerve and a RT color map superimposed on the infrared reflectance (IR) image of the peripapillary region, with a circular grid with circle diameters of 1, 2.22, and 3.45 mm manually centered on the optic nerve. The RT and RV values within the outer annulus (2.22–3.45 mm) were analyzed. (C) The OCT-based disc border (red dots) superimposed on the IR image of the peripapillary region and a 3D image of the neuroretinal rim MDB generated by our customized software. On the 3D image, yellow lines are the segmented internal limiting membrane layer. The red dots represent the OCT-based disc border, which correlates with the termination of the RPE/BM complex. The blue dots represent the cup surface points closest to the corresponding OCT-based disc border, between which forms the MDB (blue band).
Figure 1
 
Peripapillary and neuroretinal parameters investigated in this study. (A) Sample of RNFL scan centered on the optic nerve, from which RNFL thickness is obtained for analysis. (B) Illustration of how peripapillary RT and RV were obtained from volume scans of the optic nerve and a RT color map superimposed on the infrared reflectance (IR) image of the peripapillary region, with a circular grid with circle diameters of 1, 2.22, and 3.45 mm manually centered on the optic nerve. The RT and RV values within the outer annulus (2.22–3.45 mm) were analyzed. (C) The OCT-based disc border (red dots) superimposed on the IR image of the peripapillary region and a 3D image of the neuroretinal rim MDB generated by our customized software. On the 3D image, yellow lines are the segmented internal limiting membrane layer. The red dots represent the OCT-based disc border, which correlates with the termination of the RPE/BM complex. The blue dots represent the cup surface points closest to the corresponding OCT-based disc border, between which forms the MDB (blue band).
Figure 2
 
Scatter plots of age versus the global values of three peripapillary parameters and two neuroretinal rim parameters. The three peripapillary parameters are (A) RNFL thickness, (B) RT, and (C) RV. The two neuroretinal rim parameters are (D) MDB thickness and (E) MDB area.
Figure 2
 
Scatter plots of age versus the global values of three peripapillary parameters and two neuroretinal rim parameters. The three peripapillary parameters are (A) RNFL thickness, (B) RT, and (C) RV. The two neuroretinal rim parameters are (D) MDB thickness and (E) MDB area.
Figure 3
 
Bar graphs showing the racial and ethnic variations in the mean and standard deviation values of three peripapillary retinal parameters and two neuroretinal rim parameters. Asterisks represent significant difference (P < 0.05) when compared to white. Error bars represent standard deviation.
Figure 3
 
Bar graphs showing the racial and ethnic variations in the mean and standard deviation values of three peripapillary retinal parameters and two neuroretinal rim parameters. Asterisks represent significant difference (P < 0.05) when compared to white. Error bars represent standard deviation.
Table 1
 
Summary of Patient Demographics
Table 1
 
Summary of Patient Demographics
Table 2
 
Mean Normal Values for OCT Neuroretinal and Peripapillary Parameters: Rates of Age-Related Decline by Absolute Values and by Percentages
Table 2
 
Mean Normal Values for OCT Neuroretinal and Peripapillary Parameters: Rates of Age-Related Decline by Absolute Values and by Percentages
Table 3
 
Linear Regression Analysis Showing the Effects of Race and Ethnicity on the Global and Regional Values of Three Peripapillary Retinal Parameters and Two Neuroretinal Rim Parametersa,b
Table 3
 
Linear Regression Analysis Showing the Effects of Race and Ethnicity on the Global and Regional Values of Three Peripapillary Retinal Parameters and Two Neuroretinal Rim Parametersa,b
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