Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions

Jacoba A. van de Kreeke; H. Ton Nguyen; Elles Konijnenberg; Jori Tomassen; Anouk den Braber; Mara Ten Kate; Carole H. Sudre; Frederik Barkhof; Dorret I. Boomsma; H. Stevie Tan; Frank D. Verbraak; Pieter Jelle Visser

doi:10.1167/iovs.18-25341

Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions

Jacoba A. van de Kreeke, H. Ton Nguyen, Elles Konijnenberg, Jori Tomassen, Anouk den Braber, Mara Ten Kate, Carole H. Sudre, Frederik Barkhof, Dorret I. Boomsma, H. Stevie Tan, Frank D. Verbraak, Pieter Jelle Visser

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Purpose: Retinal microvasculopathy may reflect small vessel disease in the brain. Here we test the relationships between retinal vascular parameters and small vessel disease, the influence of cardiovascular risk factors on these relationships, and their common genetic background in a monozygotic twin cohort.

Methods: We selected 134 cognitively healthy individuals (67 monozygotic twin pairs) aged ≥60 years from the Netherlands Twin Register for the EMIF-AD PreclinAD study. We measured seven retinal vascular parameters averaged over both eyes using fundus images analyzed with Singapore I Vessel Assessment. Small vessel disease was assessed on MRI by a volumetric measurement of periventricular and deep white matter hyperintensities. We calculated associations between RVPs and WMH, estimated intratwin pair correlations, and performed twin-specific analyses on relationships of interest.

Results: Deep white matter hyperintensities volume was positively associated with retinal tortuosity in veins (P = 0.004) and fractal dimension in arteries (P = 0.001) and veins (P = 0.032), periventricular white matter hyperintensities volume was positively associated with retinal venous width (P = 0.028). Intratwin pair correlations were moderate to high for all small vessel disease/retinal vascular parameter variables (r = 0.49-0.87, P < 0.001). Cross-twin cross-trait analyses showed that retinal venous tortuosity of twin 1 could predict deep white matter hyperintensities volume of the co-twin (r = 0.23, P = 0.030). Within twin-pair differences for retinal venous tortuosity were associated with within twin-pair differences in deep white matter hyperintensities volume (r = 0.39, P = 0.001).

Conclusions: Retinal arterial fractal dimension and venous tortuosity have associations with deep white matter hyperintensities volume. Twin-specific analyses suggest that retinal venous tortuosity and deep white matter hyperintensities volume have a common etiology driven by both shared genetic factors and unique environmental factors, supporting the robustness of this relationship.

Original language	English
Pages (from-to)	5025-5031
Number of pages	7
Journal	Investigative ophthalmology & visual science
Volume	59
Issue number	12
DOIs	https://doi.org/10.1167/iovs.18-25341
Publication status	Published - 1 Oct 2018

Funding

We found that retinal venous tortuosity was positively associated with deep white matter hyperintensities volume. In the retina, increased vascular tortuosity is thought to be indicative of vessel wall dysfunction, tissue hypoxia, disturbed blood–retina barrier, and disturbed blood flow.52 Similar mechanisms have been described to lead to white matter hyperintensities in the brain,53 suggesting similar processes on a microvascular level are occurring in synchrony in both the eye and the brain. This was supported by cross-twin cross-trait

Funders	Funder number
EU/EFPIA	115372

Cohort Studies

Netherlands Twin Register (NTR)

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van de Kreeke, J. A., Nguyen, H. T., Konijnenberg, E., Tomassen, J., den Braber, A., Ten Kate, M., Sudre, C. H., Barkhof, F., Boomsma, D. I., Tan, H. S., Verbraak, F. D., & Visser, P. J. (2018). Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions. Investigative ophthalmology & visual science, 59(12), 5025-5031. https://doi.org/10.1167/iovs.18-25341

@article{3a7f2ab2116f4c7a8509b93f5dfe9aa3,

title = "Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions",

abstract = "Purpose: Retinal microvasculopathy may reflect small vessel disease in the brain. Here we test the relationships between retinal vascular parameters and small vessel disease, the influence of cardiovascular risk factors on these relationships, and their common genetic background in a monozygotic twin cohort.Methods: We selected 134 cognitively healthy individuals (67 monozygotic twin pairs) aged ≥60 years from the Netherlands Twin Register for the EMIF-AD PreclinAD study. We measured seven retinal vascular parameters averaged over both eyes using fundus images analyzed with Singapore I Vessel Assessment. Small vessel disease was assessed on MRI by a volumetric measurement of periventricular and deep white matter hyperintensities. We calculated associations between RVPs and WMH, estimated intratwin pair correlations, and performed twin-specific analyses on relationships of interest.Results: Deep white matter hyperintensities volume was positively associated with retinal tortuosity in veins (P = 0.004) and fractal dimension in arteries (P = 0.001) and veins (P = 0.032), periventricular white matter hyperintensities volume was positively associated with retinal venous width (P = 0.028). Intratwin pair correlations were moderate to high for all small vessel disease/retinal vascular parameter variables (r = 0.49-0.87, P < 0.001). Cross-twin cross-trait analyses showed that retinal venous tortuosity of twin 1 could predict deep white matter hyperintensities volume of the co-twin (r = 0.23, P = 0.030). Within twin-pair differences for retinal venous tortuosity were associated with within twin-pair differences in deep white matter hyperintensities volume (r = 0.39, P = 0.001).Conclusions: Retinal arterial fractal dimension and venous tortuosity have associations with deep white matter hyperintensities volume. Twin-specific analyses suggest that retinal venous tortuosity and deep white matter hyperintensities volume have a common etiology driven by both shared genetic factors and unique environmental factors, supporting the robustness of this relationship.",

author = "{van de Kreeke}, {Jacoba A.} and Nguyen, {H. Ton} and Elles Konijnenberg and Jori Tomassen and {den Braber}, Anouk and {Ten Kate}, Mara and Sudre, {Carole H.} and Frederik Barkhof and Boomsma, {Dorret I.} and Tan, {H. Stevie} and Verbraak, {Frank D.} and Visser, {Pieter Jelle}",

year = "2018",

month = oct,

day = "1",

doi = "10.1167/iovs.18-25341",

language = "English",

volume = "59",

pages = "5025--5031",

journal = "Investigative ophthalmology & visual science",

issn = "0146-0404",

publisher = "Association for Research in Vision and Ophthalmology",

number = "12",

}

van de Kreeke, JA, Nguyen, HT, Konijnenberg, E, Tomassen, J, den Braber, A, Ten Kate, M, Sudre, CH, Barkhof, F, Boomsma, DI, Tan, HS, Verbraak, FD & Visser, PJ 2018, 'Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions', Investigative ophthalmology & visual science, vol. 59, no. 12, pp. 5025-5031. https://doi.org/10.1167/iovs.18-25341

TY - JOUR

T1 - Retinal and Cerebral Microvasculopathy

T2 - Relationships and Their Genetic Contributions

AU - van de Kreeke, Jacoba A.

AU - Nguyen, H. Ton

AU - Konijnenberg, Elles

AU - Tomassen, Jori

AU - den Braber, Anouk

AU - Ten Kate, Mara

AU - Sudre, Carole H.

AU - Barkhof, Frederik

AU - Boomsma, Dorret I.

AU - Tan, H. Stevie

AU - Verbraak, Frank D.

AU - Visser, Pieter Jelle

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Purpose: Retinal microvasculopathy may reflect small vessel disease in the brain. Here we test the relationships between retinal vascular parameters and small vessel disease, the influence of cardiovascular risk factors on these relationships, and their common genetic background in a monozygotic twin cohort.Methods: We selected 134 cognitively healthy individuals (67 monozygotic twin pairs) aged ≥60 years from the Netherlands Twin Register for the EMIF-AD PreclinAD study. We measured seven retinal vascular parameters averaged over both eyes using fundus images analyzed with Singapore I Vessel Assessment. Small vessel disease was assessed on MRI by a volumetric measurement of periventricular and deep white matter hyperintensities. We calculated associations between RVPs and WMH, estimated intratwin pair correlations, and performed twin-specific analyses on relationships of interest.Results: Deep white matter hyperintensities volume was positively associated with retinal tortuosity in veins (P = 0.004) and fractal dimension in arteries (P = 0.001) and veins (P = 0.032), periventricular white matter hyperintensities volume was positively associated with retinal venous width (P = 0.028). Intratwin pair correlations were moderate to high for all small vessel disease/retinal vascular parameter variables (r = 0.49-0.87, P < 0.001). Cross-twin cross-trait analyses showed that retinal venous tortuosity of twin 1 could predict deep white matter hyperintensities volume of the co-twin (r = 0.23, P = 0.030). Within twin-pair differences for retinal venous tortuosity were associated with within twin-pair differences in deep white matter hyperintensities volume (r = 0.39, P = 0.001).Conclusions: Retinal arterial fractal dimension and venous tortuosity have associations with deep white matter hyperintensities volume. Twin-specific analyses suggest that retinal venous tortuosity and deep white matter hyperintensities volume have a common etiology driven by both shared genetic factors and unique environmental factors, supporting the robustness of this relationship.

AB - Purpose: Retinal microvasculopathy may reflect small vessel disease in the brain. Here we test the relationships between retinal vascular parameters and small vessel disease, the influence of cardiovascular risk factors on these relationships, and their common genetic background in a monozygotic twin cohort.Methods: We selected 134 cognitively healthy individuals (67 monozygotic twin pairs) aged ≥60 years from the Netherlands Twin Register for the EMIF-AD PreclinAD study. We measured seven retinal vascular parameters averaged over both eyes using fundus images analyzed with Singapore I Vessel Assessment. Small vessel disease was assessed on MRI by a volumetric measurement of periventricular and deep white matter hyperintensities. We calculated associations between RVPs and WMH, estimated intratwin pair correlations, and performed twin-specific analyses on relationships of interest.Results: Deep white matter hyperintensities volume was positively associated with retinal tortuosity in veins (P = 0.004) and fractal dimension in arteries (P = 0.001) and veins (P = 0.032), periventricular white matter hyperintensities volume was positively associated with retinal venous width (P = 0.028). Intratwin pair correlations were moderate to high for all small vessel disease/retinal vascular parameter variables (r = 0.49-0.87, P < 0.001). Cross-twin cross-trait analyses showed that retinal venous tortuosity of twin 1 could predict deep white matter hyperintensities volume of the co-twin (r = 0.23, P = 0.030). Within twin-pair differences for retinal venous tortuosity were associated with within twin-pair differences in deep white matter hyperintensities volume (r = 0.39, P = 0.001).Conclusions: Retinal arterial fractal dimension and venous tortuosity have associations with deep white matter hyperintensities volume. Twin-specific analyses suggest that retinal venous tortuosity and deep white matter hyperintensities volume have a common etiology driven by both shared genetic factors and unique environmental factors, supporting the robustness of this relationship.

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JO - Investigative ophthalmology & visual science

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Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions

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