Fundus Autofluorescence Findings in a Mouse Model of Retinal Detachment

Secondi, Roberta; Kong, Jian; Blonska*, Anna; Staurenghi, Giovanni; Sparrow, Janet R.

doi:10.1167/iovs.12-9672

Cited by 33 publications

(30 citation statements)

References 44 publications

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“…12,13 Fundus AF imaging by cSLO also has aided the characterization of retina in animal models. [14][15][16] Several therapeutic strategies aimed at alleviating vision loss in recessive Stargardt disease have been tested preclinically in Abca4 À/À and Rdh8 À/À Abca4 À/À mice. These approaches include vector-based gene therapies, 17,18 and the employment of compounds that limit the visual cycle.…”

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confidence: 99%

Quantitative Fundus Autofluorescence in Mice: Correlation With HPLC Quantitation of RPE Lipofuscin and Measurement of Retina Outer Nuclear Layer Thickness

Sparrow

Blonska*

Flynn

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Sparrow JR, Blonska A, Flynn E, et al. Quantitative fundus autofluorescence in mice: correlation with HPLC quantitation of RPE lipofuscin and measurement of retina outer nuclear layer thickness. Invest Ophthalmol Vis Sci. 2013;54:281254: -282054: . DOI:10.1167 PURPOSE. Our study was conducted to establish procedures and protocols for quantitative autofluorescence (qAF) measurements in mice, and to report changes in qAF, A2E bisretinoid concentration, and outer nuclear layer (ONL) thickness in mice of different genotypes and age.METHODS. Fundus autofluorescence (AF) images (558 lens, 488 nm excitation) were acquired in albino Abca4þ/À , and Abca4 þ/þ mice (ages 2-12 months) with a confocal scanning laser ophthalmoscope (cSLO). Gray levels (GLs) in each image were calibrated to an internal fluorescence reference. The bisretinoid A2E was measured by quantitative high performance liquid chromatography (HPLC). Histometric analysis of ONL thicknesses was performed.RESULTS. The Bland-Altman coefficient of repeatability (95% confidence interval) was 618% for between-session qAF measurements. Mean qAF values increased with age (2-12 months) in all groups of mice. qAF was approximately 2-fold higher in Abca4 À/À mice than in Abca4mice and approximately 20% higher in heterozygous mice. HPLC measurements of the lipofuscin fluorophore A2E also revealed age-associated increases, and the fold difference between Abca4 À/À and wild-type mice was more pronounced (approximately 3-4-fold) than measurable by qAF. Moreover, A2E levels declined after 8 months of age, a change not observed with qAF. The decline in A2E levels in the Abca4 À/À mice corresponded to reduced photoreceptor cell viability as reflected in ONL thinning beginning at 8 months of age.CONCLUSIONS. The qAF method enables measurement of in vivo lipofuscin and the detection of genotype and age-associated differences. The use of this approach has the potential to aid in understanding retinal disease processes and will facilitate preclinical studies.Keywords: Abca4, RPE lipofuscin, quantitative fundus autofluorescence, mouse, bisretinoid F undus autofluorescence (AF) imaging using a confocal scanning laser ophthalmoscope (cSLO) is a noninvasive approach to monitoring the natural autofluorescence of the retina generated from the bisretinoids of lipofuscin in RPE. In early studies of fundus AF in human subjects, quantitation at discrete positions on the fundus was done by noninvasive spectrophotometry. [1][2][3] This work contributed to our understanding of the relationship between RPE lipofuscin accumulation and age, and demonstrated increases in fundus AF in retinal disorders, such as recessive Stargardt disease, 3,4 caused by mutations in the ATP-binding cassette (ABC) transporter ABCA4.5 Conversely, imaging of fundus AF by cSLO records the spatial distribution of fundus AF [6][7][8][9] and is valuable as a means to monitor specific patterns of AF in human retinal diseases, including age related macular degeneration and RP.9-11 Some studies have reported comp...

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Quantitative Fundus Autofluorescence in Mice: Correlation With HPLC Quantitation of RPE Lipofuscin and Measurement of Retina Outer Nuclear Layer Thickness

Sparrow

Blonska*

Flynn

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Animals were sedated with inhaled isoflurane to effect, and the cornea was kept hydrated during imaging using ophthalmic saline eye wash. With the goal of capturing an in vivo image of the granular autofluorescent deposits previously observed by fluorescence microscopy, FAF was used to evaluate the retina. Eyes were stimulated with blue light (465-490 nm) and imaged with a yellow-green (520-530 nm) band pass filter using a 55 wide angle noncontact lens with the optic nerve head as close to the center as possible (Luhmann et al 2009;Secondi et al 2012).…”

Section: In Vivo Ocular Assessmentmentioning

confidence: 99%

Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat

Fielden

Werner

Jamison³

et al. 2014

Toxicol Pathol

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b-Secretase 1 (BACE1) represents an attractive target for the treatment of Alzheimer's disease. In the course of development of a novel small molecule BACE1 inhibitor (AMG-8718), retinal thinning was observed in a 1-month toxicity study in the rat. To further understand the lesion, an investigational study was conducted whereby rats were treated daily with AMG-8718 for 1 month followed by a 2-month treatment-free phase. The earliest detectable change in the retina was an increase in autofluorescent granules in the retinal pigment epithelium (RPE) on day 5; however, there were no treatment-related light microscopic changes observed in the neuroretina and no changes observed by fundus autofluorescence or routine ophthalmoscopic examination after 28 days of dosing. Following 2 months of recovery, there was significant retinal thinning attributed to loss of photoreceptor nuclei from the outer nuclear layer. Electroretinographic changes were observed as early as day 14, before any microscopic evidence of photoreceptor loss. BACE1 knockout rats were generated and found to have normal retinal morphology indicating that the retinal toxicity induced by AMG-8718 was likely off-target. These results suggest that AMG-8718 impairs phagolysosomal function in the rat RPE, which leads to photoreceptor dysfunction and ultimately loss of photoreceptors.

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“…Lipofuscin, a byproduct of cellular activity and stress, is believed to be the major fluorophore responsible for FAF, and accumulates within the RPE with age and disease (Boulton, Docchio, Dayhaw-Barker, Ramponi, & Cubeddu, 1990;Delori et al, 1995;Eldred & Lasky, 1993;Lamb & Simon, 2004;Sparrow et al, 2010). Recent studies show that FAF can detect abnormalities in the mouse eye caused by genetic defects and retinal damage such as photostress (Charbel Issa et al, 2012;Joly et al, 2009;Secondi, Kong, Blonska, Staurenghi, & Sparrow, 2012). However, to date FAF has not, to our knowledge, been applied to pharmacological toxicity studies.…”

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confidence: 99%

Fundus autofluorescence (FAF) non-invasively identifies chorioretinal toxicity in a rat model of retinal pigment epithelium (RPE) damage

Baek

Liang

Zhao

et al. 2015

Journal of Pharmacological and Toxicological Methods

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Fundus Autofluorescence Findings in a Mouse Model of Retinal Detachment

Cited by 33 publications

References 44 publications

Quantitative Fundus Autofluorescence in Mice: Correlation With HPLC Quantitation of RPE Lipofuscin and Measurement of Retina Outer Nuclear Layer Thickness

Quantitative Fundus Autofluorescence in Mice: Correlation With HPLC Quantitation of RPE Lipofuscin and Measurement of Retina Outer Nuclear Layer Thickness

Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat

Fundus autofluorescence (FAF) non-invasively identifies chorioretinal toxicity in a rat model of retinal pigment epithelium (RPE) damage

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