Results

Cohort Characteristics

Of the 401 enrolled Natural History and Observation Registry participants at the Department of Ophthalmology at the University of Bonn, high-quality OCT, color fundus photographs, and 2WAF images were available in 265 eyes from 220 MacTel patients (mean age at baseline 62.6 years ± 7.7 years, 60.5% female) and were analyzed. Eyes were distributed across disease stages as follows: stage 0 (38 eyes, [14.3%]), stage 1 (45 eyes, [17.0%]), stage 2 (67 eyes, [25.3%]), stage 3 (12 eyes, [4.5%]), stage 4 (24 eyes, [9.1%]), stage 5 (46 eyes, [17.4%]), and stage 6 (33 eyes, [12.5%]) with overall comparable age. For graphical comparison, we included 10 eyes of 10 healthy control patients (mean age 44.6 ± 13.7 years, 8 female, 10 phakic). Table 1 summarizes the characteristics of the MacTel eyes.

Characteristic | All | Stage 0 | Stage 1 | Stage 2 | Stage 3 | Stage 4 | Stage 5 | Stage 6
Patients | 220 | 3415.5% | 4018.2% | 5324.1% | 104.5% | 209.1% | 3716.8% | 2611.8%
Eyes | 265 | 38 | 45 | 67 | 12 | 24 | 46 | 33
Female | 133 | 16 | 20 | 33 | 6 | 13 | 25 | 12
Age | 62.6 ± 7.7 | 61.1 ± 11.2 | 62.7 ± 8.5 | 59.5 ± 9.9 | 65.0 ± 8.9 | 64.3 ± 7.4 | 64.7 ± 10.3 | 65.9 ± 11.1
Phakic | 202 | 33 | 35 | 47 | 12 | 16 | 30 | 19

Spatial MPOD Distribution across Different Disease Stages

Figure 1 exemplarily shows the OCT B-Scan, 2WAF en face MPOD images, and the MPOD histograms in a healthy eye, stage 2 MacTel, and stage 4 MacTel. Macular pigment optical density is temporally reduced in stage 2 (B2 and B3) and more globally reduced in stage 4 (C2 and C3). Pixel-wise MPOD maps demonstrated a stage-dependent characteristic alteration of MP distribution, see Figure 2. Compared to healthy eyes (A), stage 0 MacTel shows an initial temporal reduction of MP (B). Stages 1 and 2 (C + D) show similar MPOD distribution characterized by a preserved nasal–inferior bridge of MP (red arrowheads). In stages 3 and 4 (E + F), this bridge (red arrowheads) becomes less apparent due to further nasal and central depletion of MPOD. Stage 5 (G) shows marked central MP depletion, while stage 6 (H) demonstrates additional attenuation of the residual parafoveal ring.

Figure 1: Macular pigment distribution in different MacTel disease stages. A1-A3: left eye of a 56-year-old healthy male. B1-B3: left eye of a 57-year-old female, MacTel stage 2. C1-C3: left eye of a 60-year-old male, MacTel stage 4. The horizontal extent of the foveal B-scans (A1, B1, C1) is represented by the orange line in B2. The gray-scale MPOD image in A2 shows a central peak inside the central subfield of the ETDRS grid. B2 shows a temporally pronounced MPOD decrease, and C2 shows an oval-shaped area of decreased MPOD. A3, B3, and C3 show histograms of MPOD sampled from the bowtie depicted in B2. The histograms reproduce the en face shapes visible in A2, B2, and C2. MacTel = macular telangiectasia type 2; MPOD = macular pigment optical density.

Figure 2: Spatial distribution pattern of MPOD across different MacTel stages. Pixel-wise MPOD maps in healthy eyes and MacTel disease stages 0 to 6. Color scale indicates MPOD values (AU). In healthy eyes (A), MPOD demonstrates a central peak with concentric decline toward the periphery. In early MacTel (stage 0, B), a focal temporal reduction of central pigment becomes apparent. With increasing disease stage (stages 1-4, C-F), the central peak disappears and temporal MPOD is reduced further, revealing an ellipse of MPOD at 4° × 7° eccentricity. Additionally, these stages maintain a nasal–inferior bridge of preserved MPOD (red arrowheads). In advanced stages (stages 5-6, G + H), this bridge disappears, and central MPOD is reduced further. AU = arbitrary units; MacTel = macular telangiectasia type 2; MPOD = macular pigment optical density.

Spatial MPOD Distribution in ETDRS Subfields

As shown in Table 2, MPOD values differed significantly across disease stages within the central and inner ETDRS subfields (all P < 0.001), with the exception of the superior inner subfield (P = 0.065). No significant differences in MPOD were observed across MacTel stages in the outer ETDRS subfields (all P > 0.05).

ETDRS Subfield | All MacTel | Stage 0 | Stage 1 | Stage 2 | Stage 3 | Stage 4 | Stage 5 | Stage 6 | P Value | Healthy
CS | 0.063 ± 0.086 | 0.158 ± 0.134 | 0.052 ± 0.051 | 0.064 ± 0.074 | 0.066 ± 0.064 | 0.042 ± 0.045 | 0.026 ± 0.038 | 0.036 ± 0.078 | <0.001 | 0.4 ± 0.17
TI | 0.025 ± 0.034 | 0.054 ± 0.043 | 0.024 ± 0.030 | 0.032 ± 0.031 | 0.013 ± 0.021 | 0.010 ± 0.026 | 0.007 ± 0.017 | 0.016 ± 0.032 | <0.001 | 0.131 ± 0.058
II | 0.051 ± 0.031 | 0.071 ± 0.033 | 0.056 ± 0.027 | 0.057 ± 0.029 | 0.042 ± 0.026 | 0.039 ± 0.034 | 0.041 ± 0.032 | 0.037 ± 0.025 | <0.001 | 0.110 ± 0.052
NI | 0.061 ± 0.041 | 0.086 ± 0.043 | 0.063 ± 0.035 | 0.066 ± 0.037 | 0.049 ± 0.038 | 0.055 ± 0.037 | 0.051 ± 0.047 | 0.043 ± 0.032 | <0.001 | 0.120 ± 0.065
SI | 0.068 ± 0.038 | 0.080 ± 0.039 | 0.071 ± 0.035 | 0.072 ± 0.034 | 0.053 ± 0.043 | 0.073 ± 0.049 | 0.061 ± 0.040 | 0.052 ± 0.032 | 0.065 | 0.123 ± 0.050
TO | 0.035 ± 0.023 | 0.029 ± 0.021 | 0.038 ± 0.023 | 0.034 ± 0.024 | 0.037 ± 0.013 | 0.032 ± 0.023 | 0.041 ± 0.024 | 0.036 ± 0.025 | 0.244 | 0.033 ± 0.016
IO | 0.009 ± 0.012 | 0.008 ± 0.009 | 0.012 ± 0.015 | 0.011 ± 0.011 | 0.003 ± 0.006 | 0.005 ± 0.008 | 0.005 ± 0.009 | 0.009 ± 0.015 | 0.066 | 0.009 ± 0.009
NO | 0.018 ± 0.019 | 0.021 ± 0.017 | 0.016 ± 0.022 | 0.018 ± 0.021 | 0.015 ± 0.013 | 0.022 ± 0.020 | 0.018 ± 0.022 | 0.014 ± 0.016 | 0.613 | 0.030 ± 0.027
SO | 0.009 ± 0.012 | 0.006 ± 0.009 | 0.008 ± 0.013 | 0.008 ± 0.009 | 0.007 ± 0.010 | 0.012 ± 0.016 | 0.013 ± 0.031 | 0.009 ± 0.028 | 0.184 | 0.005 ± 0.055

Spatial MPOD in Stable and Progressing Eyes

A total of 232 eyes (stages 0 - 5) were available for progression analysis with a mean follow-up time of 2.5 ± 3 years. As shown in Figure 3, stable eyes show temporally reduced MPOD, whereas central and nasal areas are less affected by MPOD depletion. In progressing eyes, MPOD depletion is even more advanced temporally, and MPOD is also more reduced in nasal areas. Z-score maps show that MPOD in stable eyes is higher in the center and is surrounded by a barrier of comparatively lower MPOD. In progressing eyes, compared to the entire population, MPOD appears depleted centrally and surrounded by a barrier of higher MPOD.

Figure 3: Macular pigment optical density distribution in stable and progressing MacTel eyes. Top row (A + B): standard pixel-wise MPOD maps. Bottom row (C + D): corresponding z-score maps normalized to the cohort mean. Stable eyes (A) demonstrate a preserved parafoveal ring with relatively maintained central values, whereas progressing eyes (B) show marked central depletion with expansion of low-density areas. Z-score mapping highlights early central reduction preceding visible structural changes and emphasizes spatial progression of macular pigment loss. AU = arbitrary units; MacTel = macular telangiectasia type 2; MPOD = macular pigment optical density.

Table 3 indicates that MPOD differed statistically between stable and progressing eyes in the central and temporal inner (both P < 0.001), inferior inner (P = 0.002), nasal inner (P = 0.035), and superior outer (P = 0.019) subfield.

ETDRS Subfield | Stable (n = 139) | Progressive (n = 93) | P Value
CS | 0.077 ± 0.094 | 0.039 ± 0.061 | <0.001
TI | 0.032 ± 0.035 | 0.012 ± 0.026 | <0.001
II | 0.056 ± 0.030 | 0.043 ± 0.031 | 0.002
NI | 0.065 ± 0.039 | 0.055 ± 0.042 | 0.035
SI | 0.069 ± 0.037 | 0.066 ± 0.040 | 0.290
TO | 0.035 ± 0.023 | 0.036 ± 0.022 | 0.684
IO | 0.010 ± 0.012 | 0.007 ± 0.010 | 0.055
NO | 0.018 ± 0.019 | 0.019 ± 0.022 | 0.714
SO | 0.008 ± 0.010 | 0.011 ± 0.015 | 0.019

Spatial MPOD Associated with Disease Progression

As shown in Table 4, higher MPOD in the temporal inner ETDRS subfield decreases the risk for progression (OR 0.97 per 0.01-unit increase; 95% confidence interval (CI) 0.93 – 0.98; P = 0.006), whereas higher MPOD in the superior outer ETDRS subfield increases the risk for progression (OR 1.03 per 0.01-unit increase; 95% CI 1.01 – 1.04, P = 0.021). No significant association between MPOD in other ETDRS subfields and disease progression was observed.

ETDRS Subfield | OR | 95% CI | P Value
Intercept | 1.02 | 1.00–1.04 | 0.135
Age | 1.00 | 1.00–1.00 | 0.079
CS | 0.96 | 0.96–1.01 | 0.701
TI | 0.97 | 0.93–0.98 | 0.006
II | 1.00 | 0.99–1.00 | 0.184
NI | 1.03 | 0.96–1.05 | 0.364
SO | 1.03 | 1.01–1.04 | 0.021