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Topographical inner retinal changes in iAMD

by Matt Trinh

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PhD, M Optom, B Optom / B Sc (Hons)

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m.trinh@unsw.edu.au

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Posterior Eye Education & Research Society

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Disclosures

  • No financial disclosures.
  • Key results published in a PhD thesis and across several papers, with invaluable guidance from:
      • Prof Michael Kalloniatis and Dr Lisa Nivison-Smith

References

Posterior Eye Education & Research Society

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Objectives

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  • Appreciate spatial patterns of inner retinal change in intermediate AMD (iAMD).

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  • Discuss future directions and clinical relevance.

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References

Microsoft CoPilot 29/05/2024, Dall-E 3.

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Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important?
  • Results vary depending upon how we group data or delineate spaces, aka ecological fallacy or modifiable areal unit problem

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Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important?
  • Results vary depending upon how we group data or delineate spaces, aka ecological fallacy or modifiable areal unit problem

​

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​

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Quadrant means

5.33

5.67

6

5.89

5

9

5

6

5

6

7

5

7

6

7

5

8

1

1

5

5

6

7

1

1

5

6

7

5

6

8

5

6

7

8

9

9

5

7

5

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important?
  • Results vary depending upon how we group data or delineate spaces, aka ecological fallacy or modifiable areal unit problem
        • E.g., subtle differences can be ‘diluted’ via ‘excessive’ averaging.

​

​

​

​

​

​

​

​

Quadrant means

5.33

5.67

6

5.89

5

9

5

6

5

6

7

5

7

6

7

5

8

1

1

5

5

6

7

1

1

5

6

7

5

6

8

5

6

7

8

9

9

5

7

5

5

9

5

6

5

6

7

5

7

6

7

5

8

1

1

5

5

6

7

1

1

5

6

7

5

6

8

5

6

7

8

9

9

5

7

5

Cluster means

1

6.31

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • We see this for the inner retinal neurons.

References

Curcio, C. A. & Allen, K. A. Topography of ganglion cells in human retina. J. Comp. Neurol. 300, 5–25 (1990).

Masri, R. A. et al. Composition of the inner nuclear layer in human retina. Invest. Ophthalmol. Vis. Sci. 62, 22 (2021).

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • We see this for the inner retinal neurons.

References

Curcio, C. A. & Allen, K. A. Topography of ganglion cells in human retina. J. Comp. Neurol. 300, 5–25 (1990).

Masri, R. A. et al. Composition of the inner nuclear layer in human retina. Invest. Ophthalmol. Vis. Sci. 62, 22 (2021).

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • We see this for the inner retinal vasculature.

References

Tan, P. E. Z. et al. Quantitative confocal imaging of the retinal microvasculature in the human retina. Invest. Ophthalmol. Vis. Sci. 53, 5728–5736 (2012).

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • We see this for the inner retinal vasculature.

References

Tan, P. E. Z. et al. Quantitative confocal imaging of the retinal microvasculature in the human retina. Invest. Ophthalmol. Vis. Sci. 53, 5728–5736 (2012).

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • Yet we represent these data very coarsely, e.g., ETDRS sectors…
      • Potentially inducing the modifiable areal unit problem.
      • I.e., how much data are we overlooking?

​

Posterior Eye Education & Research Society

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Background

  • Why are spatial analyses of the retina important? Because the retina is not uniform.
  • Yet we represent these data very coarsely, e.g., ETDRS sectors…
      • Potentially inducing the modifiable areal unit problem.
      • I.e., how much data are we overlooking?

​

​

​

We perform spatial analyses of the retina to explore the nuances of iAMD changes in vivo.

  • So that we can identify where in the retina/choroid we should be targeting for:
      • Future interventions, and
      • Structural endpoints.

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Methods

  • How to overcome the modifiable areal unit problem
  • Break down the OCT thickness and OCTA vessel perfusion data into reasonably small but meaningful groups/spaces.

Instead of this…

We delineate retinal space like this

Posterior Eye Education & Research Society

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Methods

  • How to overcome the modifiable areal unit problem
  • Break down the OCT thickness and OCTA vessel perfusion data into reasonably small but meaningful groups/spaces.

We delineate retinal space like this

Adjust values for eye- and person-level factors.

Posterior Eye Education & Research Society

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Methods

  • How to overcome the modifiable areal unit problem
  • Break down the OCT thickness and OCTA vessel perfusion data into reasonably small but meaningful groups/spaces.

We delineate retinal space like this

Adjust values for eye- and person-level factors.

We then ‘de-convolute’ and analyse by any spatial definition…

Clusters

Quadrants

Eccentricity

Clock hours

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??

Thinning No change Thickening

Decreased VP Increased VP

RNFL

GCL

IPL

INL

~6.9mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??
    • OCTA:
      • Superficial slab decreased perfusion; with nasal sparing??

​

Superficial

B

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??
    • OCTA:
      • Superficial slab decreased perfusion; with nasal sparing??
      • Deep slab decreased VP, diffuse.

​

Deep

B

Thinning Thickening

Decreased VP No change Increased VP

Posterior Eye Education & Research Society

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Results

  • Cross-sectional studies comparing iAMD vs normal eyes
    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??
    • OCTA:
      • Superficial slab decreased perfusion; with nasal sparing??
      • Deep slab decreased VP, diffuse.

​

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

Posterior Eye Education & Research Society

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Results

  • Summary
    • Inner retina displays patterns of structural differences in iAMD, biased superiorly.

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​

​

​

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

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Discussion

  • Summary
    • Inner retina displays patterns of structural differences in iAMD, biased superiorly.

​

    • OCT:
      • RNFL thinning.
      • GCL thinning, more so para-centrally and superiorly.
      • IPL thinning, more so para-centrally and superiorly.
      • INL thinning, more so para-centrally; and thickening??
    • OCTA:
      • Superficial slab decreased perfusion; with nasal sparing??
      • Deep slab decreased VP, diffuse.

​

​

​

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

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Discussion

  • Why?
      • INL thickening??
    • Central INL thickening – probably an artefact, almost non-existent cellular population within ~1mm eccentricity.
      • Artefact of underlying drusen distortion?

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​

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References

Masri, R. A. et al. Composition of the inner nuclear layer in human retina. Invest. Ophthalmol. Vis. Sci. 62, 22 (2021).

Thinning Thickening

Decreased VP No change Increased VP

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Discussion

  • Why?
      • INL thickening??
    • Central INL thickening – probably an artefact, almost non-existent cellular population within ~1mm eccentricity.
      • Artefact of underlying drusen distortion?
    • Extra-macular INL thickening – inner retinal remodelling? As seen in some outer retinal degenerations.
      • E.g., rod bipolar dendrite and horizontal and amacrine cell neurite outgrowth, upregulation of Müller cells.

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​

​

Thinning Thickening

Decreased VP No change Increased VP

References

Masri, R. A. et al. Composition of the inner nuclear layer in human retina. Invest. Ophthalmol. Vis. Sci. 62, 22 (2021).

Sullivan, R. K. P., WoldeMussie, E. & Pow, D. V. Dendritic and synaptic plasticity of neurons in the human age-related macular degeneration retina. Invest. Ophthalmol. Vis. Sci. 48, 2782–2791 (2007).

Fariss, R. N., Li, Z.-Y. & Milam, A. H. Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa. Am. J. Ophthalmol. 129, 215–223 (2000).

Madigan, M. C., Penfold, P. L., Provis, J. M., Balind, T. K. & Billson, F. A. Intermediate filament expression in human retinal macroglia. Histopathologic changes associated with age-related macular degeneration. Retina 14, 65–74 (1994).

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Discussion

  • Why?
      • Vascular perfusion nasal sparing?
    • Probably the radial peripapillary capillary plexus (RPCP), corresponding to the RNFL vascular plexus.
      • Unlikely to be large arterioles/venules since we skeletonised vessels (i.e., all vessels had equal contribution).

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Posterior Eye Education & Research Society

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Discussion

  • Why?
      • Vascular perfusion nasal sparing?
    • Probably the radial peripapillary capillary plexus (RPCP), corresponding to the RNFL vascular plexus.
      • Unlikely to be large arterioles/venules since we skeletonised vessels (i.e., all vessels had equal contribution).

​

      • But why?
        • Wish I knew…

​

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

​

Posterior Eye Education & Research Society

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Discussion

    • So why is the inner retina affected in iAMD?
      • Maybe anterograde degeneration, and/or systemic vascular/inflammatory pathway.

​

​

Posterior Eye Education & Research Society

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Discussion

    • So why is the inner retina affected in iAMD?
      • Maybe anterograde degeneration, and/or systemic vascular/inflammatory pathway.

​

    • So far, we’ve shown these neuronal and microvascular differences in a cross-section between groups.
      • Mixed cause-and-effect?
        • Maybe compromised inner retina (or inner retinal supply) predisposes patients to AMD?

​

​

Posterior Eye Education & Research Society

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Discussion

    • So why is the inner retina affected in iAMD?
      • Maybe anterograde degeneration, and/or systemic vascular/inflammatory pathway.

​

    • So far, we’ve shown these neuronal and microvascular differences in a cross-section between groups.
      • Mixed cause-and-effect?
        • Maybe compromised inner retina (or inner retinal supply) predisposes patients to AMD?
      • Unmeasured/unadjusted confounding?
        • Maybe there are some unaccounted systemic diseases/drugs associated with the inner retinal changes.

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​

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Spatial retinal image analyses

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Further understanding AMD

via longitudinal studies

Spatial retinal image analyses

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

Understanding AMD

via cross-sectional studies

Further understanding AMD

via longitudinal studies

Spatial retinal image analyses

E.g., what comes first, neuronal or vascular change?

SVC

RNFL

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

Understanding AMD

via cross-sectional studies

Further understanding AMD

via longitudinal studies

Spatial retinal image analyses

E.g., what comes first, neuronal or vascular change?

SVC

RNFL

E.g., how does the choroid topographically change?

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Predictive modelling for

clinical translation

Spatial retinal image analyses

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Predictive modelling for

clinical translation

Spatial retinal image analyses

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Predictive modelling for

clinical translation

Spatial retinal image analyses

E.g., can spatially-defined biomarkers (location and extent) improve prognostication of AMD?

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Predictive modelling for

clinical translation

Spatial retinal image analyses

E.g., can spatially-defined biomarkers (location and extent) improve prognostication of AMD?

Posterior Eye Education & Research Society

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Future directions + �clinical relevance

References

Microsoft CoPilot 29/05/2024, Dall-E 3.

Understanding AMD

via cross-sectional studies

Predictive modelling for

clinical translation

Spatial retinal image analyses

E.g., can spatially-defined biomarkers (location and extent) improve prognostication of AMD?

Superficial slab

Posterior Eye Education & Research Society

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Summary

​

  • Appreciate spatial patterns of inner retinal change in iAMD.

​

​

​

​

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2.

Posterior Eye Education & Research Society

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Summary

​

  • Appreciate spatial patterns of inner retinal change in iAMD.

​

  • Discuss future directions and clinical relevance.
      • Longitudinal studies to explore cause-and-effect.
      • Diagnostic and prognostic modelling to explore clinical utility.

​

​

​

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2.

Posterior Eye Education & Research Society

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Summary

​

  • Appreciate spatial patterns of inner retinal change in iAMD.

​

  • Discuss future directions and clinical relevance.
      • Longitudinal studies to explore cause-and-effect.
      • Diagnostic and prognostic modelling to explore clinical utility.

​

​

​

Thank you.

Thinning No change Thickening

Decreased VP Increased VP

SVC

DVC

RNFL

GCL

IPL

INL

~6.9mm

~6mm

References

Figure cropped from Cabral, Diogo, Ana C. Fradinho, Telmo Pereira, Meera S. Ramakrishnan, Tommaso Bacci, Dong An, Sandra Tenreiro, Miguel C. Seabra, Chandrakumar Balaratnasingam, and K. Bailey Freund.

“Macular Vascular Imaging and Connectivity Analysis Using High-Resolution Optical Coherence Tomography.” Translational Vision Science and Technology 11, no. 6 (June 1, 2022): 2. https://doi.org/10.1167/tvst.11.6.2.

Posterior Eye Education & Research Society